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2   Odyssey
              The Fight against
                                W   R   I   T   T   E   N   B   Y
                                J e f f         W o r l e y

                                        rederick Schmitt, a professor of neurol-
                                        ogy at the University of Kentucky, has
                                        two framed photographs on his office
                               walls in UK’s Sanders-Brown Center on Aging.
                               One is an M.C. Escher print in which water
                               seems to run uphill, playing tricks on percep-
                               tion; stairways defy spatial sense and lead
                               back only to themselves. Directly across from
                               this, I see the famous Salvadore Dali self-por-
                               trait. Dali’s face is a skewed and melting clock,
                               his moustache the two clock-hands.
                                 Both of these surrealistic pieces must ap-
                               proximate what it feels like to be in the grip of
                               Alzheimer’s disease. The world is suddenly
                               not what it’s always been. Time warps. Every-
                               day objects are otherworldly and disconcert-
                                 My father, late in second-stage Alzheimer’s,
                               would pick up a paperweight given to him for
Frederick Schmitt,
                               his many years as president of the Wichita
a professor in UK’s
                               Stamp Club and turn it over and over, trying to
Department of Neurol-
                               figure out what it was and what it was doing
                               there on his nightstand. In the small house he
ogy and Sanders-Brown
                               shared with my mother, he began to regularly
Center on Aging, headed
                               see his mother, dead 30 years, drifting through
up the university’s part
                               the hallways at night.
of a recent clinical study
                                 By now, almost everyone reading these words
of memantine, an FDA-
                               has lost a grandfather, a grandmother, a father,
approved drug that
                               a mother, a sibling, or friend to the all-demand-
slows deterioration
                               ing claims of Alzheimer’s.
in cognition and the
                                 As the baby boomers have aged, the number
ability to perform daily       of people in this country with Alzheimer’s
activities for patients with   disease and related disorders has grown. Newly
dementia.                      published research suggests that 4.5 million
                               Americans now have Alzheimer’s and that the
                               numbers will swell to as many as 16 million by
                               mid-century unless a cure is found.
                                 Here are a couple of other facts about
                               Alzheimer’s. The disease now strikes more

                                                University of Kentucky        3
              William Markesbery, with help from Ann Tudor in the Sanders-Brown
              Center on Aging, examines brain tissue from a patient with probable
              Alzheimer’s disease. Markesbery has been researching the causes of
              dementia for over 30 years at UK.

                                                                                    Can a Combination of
                                                                                    Vitamin E and Selenium
                                                                                    Prevent Alzheimer's?
                                                                                    William Markesbery, the University of
                                                                                    Kentucky’s patriarch of Alzheimer’s dis-
                                                                                    ease research and director of the UK
                                                                                    Alzheimer’s Disease Research Center
                                                                                    (ADRC), believes the key to Alzheimer’s
                                                                                    disease is prevention. He also believes
                                                                                    that vitamin E is an important part of
                                                                                    this key. And though he is an uncom-
              than one in 30 Americans, slowly causing memory loss,                 monly soft-spoken man, he wants his E-
              confusion, and, ultimately, death. Incidence increases                message to get out loud and clear.
                                                                                       “So far, vitamin E has emerged as one
              with age—about half the population that lives past 85
                                                                                    of the weapons we have against de-
              gets Alzheimer’s. And the disease is the third most costly
                                                                                    mentia,” Markesbery says from his of-
              in the United States, each year draining $100 billion                 fice in the Sanders-Brown Center on
              from the U.S. economy.                                                Aging, where he has served as director
                How and why do we get Alzheimer’s disease? Why do                   since 1979. “There are several other
              our brains betray us?                                                 things you can do to lower your risk of
                For over 30 years the University of Kentucky Sanders-               getting Alzheimer’s, but vitamin E taken
                                                                                    in conjunction with vitamin C is impor-
              Brown Center on Aging has been working to under-
                                                                                    tant—a previous study showed that vi-
              stand the mechanisms of Alzheimer’s, always with an                   tamin E is one factor that slows, slightly,
              eye toward prevention. Dozens of projects carried out                 the progression of the disease. The im-
              through the Alzheimer’s Disease Research Center have                  portant thing for individuals at risk is to
              made important inroads to our understanding of the                    take vitamin E and vitamin C along with
              disease—who gets Alzheimer’s and why—and research                     folic acid prior to getting the disease.”
                                                                                       So what are these risk factors?
              in 2004 continues at a vigorous pace.
                                                                                       A major factor is age: The risk of
                The projects discussed in the following pages are all               developing Alzheimer’s increases with
              concerned with a common goal: prevention and—in                       age. One out of every 10 persons 65
              the longer run with the pooled knowledge of research-                 years and older is a victim of Alzheimer’s
              ers worldwide—cure of this devastating and dehuman-                   disease, although some victims may be
              izing disease.                                                        in their 40s and 50s. Approximately 20

4   Odyssey
“You just can’t overstate the importance of prevention.
Alzheimer’s disease starts many years before it ever
shows up clinically.”                        —William Markesbery

percent of Americans between the ages         oxidative stress.                              located in Kentucky, including Central
of 75 and 84, and almost half of those 85        “What is oxidative stress?”                 Baptist Hospital in Lexington and the
years and older suffer from Alzheimer’s       Markesbery asks rhetorically. “Well, we        UK Markey Cancer Center.
disease.                                      obviously need oxygen to live, but the            Men may qualify to participate in this
   Other risk factors under study are         reactions that oxygen undergoes in the         study if they are age 62 or older (60 or
traumatic head injury, low education          body have to be carefully controlled or        older if of Hispanic or African origin)
attainment, early low linguistic skills,      else your body begins to produce oxy-          and in general good health. Participants
high-fat and high-caloric intake, and         gen radicals that damage lipids, pro-          must also have no history of diagnosed
genetics. What scientists are now call-       teins and DNA in cells, especially             dementia and no major head injury in
ing “incipient” Alzheimer’s—the earli-        neurons.”                                      the last two years.
est onset of the disease regardless of           This current project, which is called          “Prospective participants take a men-
age—has been clearly shown to be ge-          PREADVISE (Prevention of Alzheimer’s           tal status examination, and they have to
netic in origin. Three genes, Markesbery      Disease by Vitamin E and Selenium),            score in the normal range on that,”
explains, account for less than 2 per-        will link up with SELECT (Selenium             Markesbery explains. “And there’s an
cent of cases of those with early-onset       and Vitamin E Cancer Prevention Trial),        intake assessment where they’re asked
Alzheimer’s disease.                          a large National Cancer Institute-spon-        a lot of questions, especially about their
   People in all of these at-risk catego-     sored study looking at the effects of          family history.” Participants are then
ries may benefit from a study                 these two substances in preventing pros-       placed randomly into one of four
Markesbery is currently heading up.           tate cancer.                                   groups: They get either vitamin E or
Funded by a $5 million grant from the            The five-year PREADVISE study will          selenium, vitamin E and selenium, or a
National Institute on Aging, the study        examine a subgroup of about 10,000 of          placebo.
will pair vitamin E with selenium, an         the more than 32,000 men being re-                “We’re in the very early stages of this
essential trace element found in all cells    cruited nationally for SELECT.                 12-year-long trial,” says Markesbery,
and tissues in the body. Selenium is             “Like prostate cancer, Alzheimer’s          “and the key right now is active recruit-
found in water and food—seafood,              disease usually occurs later in life, so       ing. Obviously the assessment of all the
meats and Brazil nuts, for example.           this study presents a unique opportu-          data we get won’t occur for some time,
Vitamin E is found in a wide range of         nity to assess the impact of selenium          but we will get updates along the way
foods, especially vegetables, vegetable       and vitamin E on the beginnings of             on how we’re doing.”
oils, nuts, and egg yolks.                    dementia,” Markesbery says.                       The PREADVISE study is one ex-
   There is prior evidence that enhanced         So far, more than 400 locations in the      ample, he says, of how basic laboratory
levels of selenium in the brain might         United States, Canada and Puerto Rico          data from many Sanders-Brown studies
increase antioxidant defense mecha-           have enrolled men in SELECT. Study             is being translated to preventive studies
nisms against Alzheimer’s disease.            investigators hope to recruit all the par-     in Alzheimer’s disease. “You just can’t
Taken together, Markesbery says, these        ticipants during the first five years of the   overstate the importance of prevention.
two natural antioxidant supplements           trial, so each man can be followed for         This disease starts many years before it
might work better than alone in fighting      at least seven years. Five study sites are     ever shows up clinically.”

                                                                                             University of Kentucky                 5
                                                                          A New Focus on “Mild
                                                                          Cognitive Impairment”
                                                                          Detection of the earliest phase of
                                                                          memory decline has become so impor-
                                                                          tant that there is now a term used to
                                                                          describe this fairly new research focus:
                                                                          mild cognitive impairment, or MCI.
                                                                             “This phase is marked by memory
                                                                          complaints that become more pro-
                    continued from p. 3
                                                                          nounced as time goes by,” says Stephen
                                                                          Scheff, a professor of anatomy and neu-
                                                                          robiology at the Sanders-Brown Center
                                                                          on Aging. Several Sanders-Brown re-
                                                                          searchers, Scheff among them, are now
                                                                          working to better understand MCI, work
                                                                          that is made possible by the UK ADRC
                                                                          and its control group of volunteers.
                                                                          These participants, many of whom are
                                                                          spouses or relatives of an Alzheimer’s
                                                                          victim, are neurologically normal and
                                                                          in the interest of science have volun-
                                                                          teered to be research subjects. The con-
              Stephen Scheff, a professor of anatomy and neurobiology
                                                                          trol group is headed up by David
              at UK, is focusing his work on mild cognitive impairment,   Wekstein, associate director of Sand-
              the earliest phase of memory decline.                       ers-Brown.
                                                                             In this group of over 400 people, about
                                                                          half are at high risk of developing
                                                                          Alzheimer’s because of their family his-
                                                                          tory—about 30 to 40 percent of cases
                                                                          are thought to be hereditary, according
                                                                          to Markesbery. All of these subjects have
                                                                          agreed to donate their brains after they
                                                                          die (see sidebar on p. 9).
                                                                              “These participants undergo exten-
                                                                          sive cognitive testing and represent a

6   Odyssey
“The best way to keep your synapses functioning
normally is to keep your brain very active—what I
call ‘low-impact mental aerobics.’ In the shower,
say your ABCs backwards or do a math problem.
Learn a foreign language. Learn to play a musical
instrument. And keep as physically healthy as you
can.”       —Stephen Scheff

unique resource for research into the        way to measure possible memory loss          with what we see in their brain tissue.
relation between neuropathologic             is to give the patient a list of words and   We can then determine whether or not
changes and cognitive performance in         ask him, five or 10 minutes later, to        the person had MCI.”
aging,” Scheff says. He adds that partici-   recall the list. People with MCI show a         Scheff closely studies the brains of
pants in the control group who show          deficit in delayed recall, Scheff says,      those who are determined to have had
significant cognitive changes or who         and some researchers believe this might      MCI at the time of death, focusing on
develop dementia continue to be ac-          be the beginning of Alzheimer’s dis-         what he calls “synaptic connectivity.”
tively followed by the ADRC.                 ease.                                           “You are born with essentially all the
    “By studying this normal group of           In addition to talking to people in the   neurons you’re ever going to have. What
volunteers, we’re getting closer to be-      control group who report possible slight     develops is the connectivity, through
ing able to detect the earliest possible     memory loss, Scheff also gathers neu-        synapses, between different portions of
onset of the disease, and we believe         rological evidence of MCI. An expert in      the brain. You have trillions of synapses,
that with early preventive treatment,        brain anatomy, he has performed brain        and you lose and regain them every
we can slow the progression of the           autopsies for the past 16 years at Sand-     day—your brain is constantly remodel-
disease,” he says.                           ers-Brown.                                   ing as you learn new things,” Scheff
   Scheff is among the vanguard of re-          “I’m a neuroanatomist,” Scheff says.      explains.
searchers in the country involved in         “I’ve been teaching brain anatomy in            Early on in this work, he focused on
this relatively new NIH initiative. “We      the College of Medicine here for over        several areas in the cortex, association
can learn a lot from looking at end-         23 years.” He is part of the UK autopsy      areas that, like tiny assembly plants, put
stage Alzheimer’s, but the focus has         team, which also includes Markesbery,        together a lot of information. These ar-
shifted somewhat to trying to under-         who collect particular pieces of tissue      eas are where higher-order learning
stand what happens in early stages of        that researchers need to analyze. These      takes place, Scheff says, and Alzheimer’s
the disease.” Working with Scheff at         tissues are used by UK researchers as        disease especially likes to attack these
Sanders-Brown are Frederick Schmitt          well as scientists at other institutions     parts of the cortex.
and Doug Price, who Scheff character-        around the country. “We’re a brain              Using stereology, a mathematical way
izes as “an indispensable research tech”     bank,” Scheff says. “We store lots of        to estimate the total number of objects
who has been with him for 17 years.          tissue, and we share it with other ADRCs     using a 3-D model, Scheff can deter-
   Some of these control subjects will       doing excellent research since we’re         mine the number of synapses in these
begin to show some declines in cogni-        all working to solve the Alzheimer’s         association areas. “What we’ve found is
tive ability. “Typically, these are indi-    puzzle.”                                     that in Alzheimer’s disease there is a
viduals who function normally all day           Some of the brain tissue Scheff stud-     significant loss of synapses, and the
long,” Scheff says, “but have a memory       ies comes from people in the control         Alzheimer’s brain doesn’t seem to be
problem in one particular area. It’s a       group who have been followed by Sand-        capable of replacing these lost connec-
small loss of memory that might mani-        ers-Brown researchers for as long as 10      tions.” Scheff, with several colleagues
fest itself in, for example, delayed re-     years. “We go back and review the clini-     at Sanders-Brown, has published pa-
call, and we can test this.” A standard      cal charts and then combine this data        pers extensively on this work.

                                                                                          University of Kentucky                  7
   More recently, he has focused on
another area of the brain—the hippo-
campus. This is the curved, elongated
ridge of brain tissue located behind the
ear that has long been thought of as
critical for memory.
   “This is the area of the brain used for
learning and memory, and it’s been in
the popular press a lot lately. We’ve
                                             if there is a relationship between the
                                             levels of free radicals and changes in
                                             number of synapses.
                                                Echoing Markesbery, Scheff says that
                                             prevention remains the key. What can
                                             you do to keep synapse activity normal
                                             and strong?
                                                “Even though it’s true that the highest
                                             risk factor for getting Alzheimer’s is ag-
                                                                                          How Do Enzymes Fit
                                                                                          into the Alzheimer's
                                                                                          While Scheff is busy studying synaptic
                                                                                          connectivity, Louis Hersh is working to
                                                                                          better understand another kind of con-
                                                                                          nection: enzyme activity and amyloid
                                                                                          beta (A-beta) protein deposits in the
                                                                                          brain. In dozens of projects both out-
gotten tissue from people in the control     ing, we’ve found that if you are well
                                                                                          side and inside of a living organism,
group who have died, and some of             educated and you take care of yourself,
                                                                                          scientists in the past 20 years have
these individuals were tagged as hav-        even people in their late 80s and 90s
                                                                                          found that A-beta protein deposits are
ing mild cognitive impairment. In ana-       don’t show the loss of synapses and,
                                                                                          a major component of senile plaques
lyzing their brain tissue, we’ve found       therefore, don’t necessarily get
                                                                                          in Alzheimer’s-diseased brains. These
that people with MCI tend to have a          Alzheimer’s,” Scheff says. “Everybody
                                                                                          plaques and neurofibrillary tangles
significant loss of synapses in the hip-     used to think that if you live long
                                                                                          (shriveled strands resembling bundles
pocampus.”                                   enough, you’re going to get Alzheimer’s.
                                                                                          of straw inside damaged neurons) are
   Being able now to count and mea-          We don’t believe that anymore.
                                                                                          strong signatures of the disease. Recent
sure synapse loss is an important step to       “The best way to keep your synapses
                                                                                          data suggests that the A-beta protein
understanding the mechanisms of              functioning normally is to keep your
                                                                                          may also be toxic to cells before it
Alzheimer’s, but even more important,        brain very active—what I call ‘low-im-
                                                                                          forms deposits.
Scheff says, is to learn why this degrada-   pact mental aerobics.’ In the shower,
                                                                                             So how do you stop A-beta deposits
tion happens.                                say your ABCs backwards or do a math
                                                                                          from forming?
   “We’ve been dealing with this re-         problem. Learn a foreign language.
                                                                                             Hersh, professor and chairman of the
search challenge head-on for years here      Learn to play a musical instrument.
                                                                                          Department of Biochemistry in UK’s
at UK,” Scheff says. “We’ve looked at all    And keep as physically healthy as you
                                                                                          College of Medicine, believes that two
kinds of toxins as well as free-radical      can.”
                                                                                          enzymes—neprilysin and insulysin—
activity. And a part of my work is to see
                                                                                          might help do exactly that. “These two
                                                                                          enzymes have received the most atten-
                                                                                          tion as A-beta-clearing proteins,” he
                                                                                             Like firefighters off at the alarm bell,
                                                                                          enzymes marshal their forces when the
                                                                                          call comes. Their job is to move to the
                                                                                          scene of action as quickly as possible to

8   Odyssey
                                                              The BRAiNS Program
                                                               David Wekstein can’t ever count on a good night’s sleep.
                                                                 “My phone might ring at midnight, at 3 a.m., anytime really.
                                                               And I have to be ready, along with other researchers here in the
                                                               ADRC (Alzheimer’s Disease Research Center), to get moving,”
                                               says Wekstein, associate director of UK’s ADRC and Sanders-Brown Center on
                                                  The most recent caller was a close friend of someone in the BRAiNS
                                               (Biologically Resilient Adults in Neurological Studies) program who had just
start chemical reactions the body needs        died. Within an hour of the call, the body was on its way to the University of
to stay in balance and keep going. En-         Kentucky, where researchers immediately performed an autopsy. Both the
zymes are enablers.                            caller and his friend were part of a group of older Lexington-Fayette County
   The most recent and compelling              residents who have agreed to donate their brains after they die to help
evidence that neprilysin is an A-beta          researchers learn more about Alzheimer’s disease.
regulator comes from research with                Most agree to participate in the control group because they have personal
“knockout” mice, who have had this             knowledge of Alzheimer’s. They’ve lost a relative or a friend to the disease,
enzyme removed. “In these mice, A-beta         which afflicts an estimated 4.5 million people in the United States over the age
peptide levels go up,” says Hersh, who         of 65, including an estimated 60,000 Kentuckians.
has studied neprilysin for over 25 years          Jim Geddes, a UK associate professor of anatomy and neurobiology, says
through a variety of projects. “We take        that because the brain deteriorates so quickly after death, it’s vital that an
this as evidence that neprilysin normally      autopsy be performed as soon as possible. “The support of family and friends
breaks down these A-beta peptides, and         has been tremendous. We are often able to do an autopsy within three hours
when the enzyme isn’t there or                 of death,” Geddes says. “This does mean coming in at all hours of the night
decreases in amount, the A-beta levels         sometimes, but luckily we have a dedicated group of neuropathologists and
go up, and that’s not good.” He adds           researchers who do that.”
that although mice don’t naturally make           Since it opened its doors in 1985, UK’s ADRC has diagnosed and followed
amyloid deposits as the human brain            hundreds of older people with non-treatable memory disorders—mostly
does (which is probably why mice don’t         Alzheimer’s disease. Wekstein has directed the BRAiNS program since its
get Alzheimer’s), many of the same             beginning in 1989.
enzymes, such as neprilysin, are present          But studying the brains of Alzheimer’s patients alone is not enough, Wekstein
in both mice and humans.                       says. “We can study Alzheimer’s brains for the next 20 years, but if we don’t
   Insulysin has also shown itself in the      study brains of people who don’t have the disease, we can’t draw valid
past few years to be a mighty A-beta           conclusions.” This is why in 1989 he began recruiting people for a control
regulator, so Hersh’s lab has turned its       group. To date the center has recruited over 700 normal older persons, many
attention to this first cousin of neprilysin   of whom are at high risk of developing Alzheimer’s disease because of their
(both have a metal ion and contain             family history and other reasons. All of these subjects have agreed to donate
some zinc).                                    their brains at their death.
   “Enzymes work on and break down                “The Sanders-Brown brain bank is one of the most respected and highly
small molecules, and whatever an               regarded in the country,” says UK pharmacologist Eric Blalock, whose re-
enzyme goes to work on is called its           search is based on brain samples he receives from the ADRC. “Very few
substrate,” Hersh explains. “For example,      Alzheimer’s disease research centers have the kind of rapid-response team we
digestive enzymes work on many                 have.”
substrates—think about the variety of             For additional information on BRAiNS, contact Wekstein at 859/323-6040 or
food you eat in one day.” The A-beta           at

continued on p. 10

                                                                                      University of Kentucky                 9
Louis Hersh in UK’s College of
Medicine is focusing his work on
two enzymes—neprilysin and
insulysin—that team up to clear
away dangerous amyloid beta
deposits in the brain.

                                                                                        excited about right now.” Hersh hopes
                                                                                        this research will lead to clinical trials
                                                                                        in about five years.

                                                                                        Jeffrey Keller never thought his years
                                                                                        of research training would lead to an
                                                                                        intense study of garbage, but, he says,
                                                                                        that’s just what’s happened.
                                                                                           “Cells, like people, generate gar-
                                                                                        bage, and all cells have to remove it.
                                                                                        In order to keep this clutter at a non-
                                                                                        dangerous level, cells rely on one par-
peptide, it turns out, is a substrate for    than an overproduction, what’s hap-        ticular intracellular enzyme, called the
insulysin, so insulysin and neprilysin       pening is an ‘under-clearance,’” says      proteasome,” explains Keller, a UK
have a common enemy.                         Hersh. “The activity of the enforcer en-   assistant professor of anatomy and
   One very important recent finding in      zymes is somehow lessened, which al-       neurobiology whose research at Sand-
Hersh’s lab is that these two enzymes        lows the damaging effects of A-beta to     ers-Brown is focused on understanding
work to stop A-beta in different but         go relatively unchecked.”                  the work of this essential enzyme. Think
complementary ways.                             This realization has moved Hersh’s      of proteasome as the cell’s chief gar-
   “The reason neprilysin has been so        work into a new direction, he says.        bage collector.
widely studied is because it’s one of the    With continued funding through the            The garbage under scrutiny is mainly
few enzymes that work on the surface of      Alzheimer’s Association and the Na-        oxidized or mis-folded proteins, and
the cell, on the cell membrane. A-beta       tional Institute of Aging, he’s looking    since accumulations of this substance
peptides are secreted from the cell. So      now at various ways to increase the        have been implicated in Alzheimer’s
neprilysin can go to work on A-beta as       activity in the brain of these two key     disease, Huntington’s disease and
it’s being secreted or as it’s beginning     enzymes.                                   stroke, Keller’s research might help pro-
to travel into extra-cellular space.”           “We’ve never lost sight of the poten-   vide important clues to the etiology of
Insulysin, on the other hand, works in-      tial clinical applications of what we’re   these diseases.
side the cell, so there’s a sort of tag-     doing,” Hersh says. “We’re looking at a       Scientists think they have a handle
team approach to stopping A-beta in          number of approaches to utilize these      on what the enzyme generally does but
its tracks.                                  enzymes to break down A-beta both in       very little is known about the exact
   It used to be thought, Hersh says, that   the brain and elsewhere in the body.       expression of proteasome activity in
as we age we overproduce A-beta, that        We’re just starting work with a biotech    the normal and diseased brain, and
it overwhelms the cell. There is evi-        company to screen chemical libraries       even less is known about the possible
dence now to the contrary.                   to see if we can find drugs that will      role of proteasome inhibition in cell
   “We’re starting to believe that rather    activate insulysin. That’s what I’m most   death, says Keller, who spent one year

10   Odyssey
                                             “Our lab is trying to understand exactly what
                                             the garbage disposal in the brain looks like
                                             when it’s operating normally and what it
                                             looks like when it goes bad. We’re also
as a postdoc at Sanders-Brown after
earning his doctorate here in molecu-        interested in understanding what causes it
lar and cellular biology in 1998.
   “Our lab is trying to understand ex-      to stop functioning normally as we age.”
actly what the garbage disposal in the
brain looks like when it’s operating          —Jeffrey Keller
normally and what it looks like when it
goes bad. In addition, we’re interested
in understanding what causes it to stop      and its toxicity in a matter of days instead of months. We can
functioning normally as we age, or in        then apply this knowledge to the animal models of disease,
age-related disease.”                        and even the actual tissue from human disease.”
   In his studies Keller uses basic mo-        Keller admits that this approach is extremely challenging,
lecular techniques, called the reverse       not because of their methodology but because of what he
transcriptase polymerase chain reac-         calls “the numbers game.”
tion (or RT PCR), in cellular, animal          “Proteasome is so complex. At its heart, it’s a structure
and human tissue.                            made up of 28 different proteins. There are at least 82
   “Using RT PCR, we are able to visual-     additional proteins that can combine in different ways to
ize or quantify the expression of indi-      comprise this 28-protein complex. Every cell has a smorgas-
vidual proteasome subunits,” Keller          bord of choices to assemble its garbage disposal.” The
says. “This is a common way of investi-      bottom-line goal of this work, he says, is to differentiate the
gating gene expression. When we              changes that occur with normal aging from the changes that
couple this with our ability to isolate      occur with Alzheimer’s disease.
and purify the proteasome enzyme, we           Keller says his lab is making good progress in “getting
have very powerful techniques for ex-        proteasome to give up its secrets,” and that any success is
ploring the proteasome in aging and          due to the various collaborations in the Center on Aging:
age-related disease.”                        Allan Butterfield (chemistry and Center of Membrane Sci-
   In this work, he and his co-investiga-    ences), Harry Levine (Center on Aging), Rodney Guttman
tors are utilizing yeast, which, he says,    (gerontology Ph.D. program), and Jim Geddes (anatomy
looks a lot like human brain tissue.         and neurobiology). “They’re experts in different areas of
“Remarkably, the pattern of proteasome       neuroscience, and we are able to apply their skills to our
expression and the process of oxida-         project. And of course Dr. Markesbery, who’s at the center
tive stress are similar in yeast and hu-     of all of the work we do here,” Keller adds.
man tissue. The advantage of using yeast       Keller is at the halfway point in this work, which is being
lies in the power of genetics—we can         supported by the National Institute of Aging for $1 million
rapidly and directly test the role of spe-   for four years and by other grants from the National Insti-
cific genes in regulating the proteasome     tutes of Health and private foundations.

                                                                                           U n i v e r s i t y o f K e n t u c k y 11
                                             “The most important thing to come out of
                                             our recent work is that we have identified
                                             hundreds of genes that correlated with the
                                             early phase of Alzheimer’s. Then we were

                                             able to assign identified genes to biological
                                             process categories to get an idea of which
                                             cellular pathways were being turned on.”
                                             —Philip Landfield

Microarrays: Chipping                        nology used in the manufacture of high-      scanning technology.
Away at the Mysteries                        performance computer chips like Intel           “When a laser is focused on a highly
of Alzheimer's Disease                       Pentium processors).                         bound region of the chip, it shines more
                                                In Landfield’s project, human brain       brightly than on an unbound region, so
Genes, like enzymes, are also role-play-
                                             tissue from UK’s ADRC was used to            by measuring the light intensity, we can
ers, and molecular biologists continue
                                             analyze gene activity based on chips         quantify the amount of binding and,
to spend long hours in the lab working
                                             made by Affymetrix, a Santa Clara-based      therefore, the amount of mRNA in the
to shed light on these various roles.
                                             company. The UK group analyzed the           tissue,” Landfield explains. In this way,
Traditional methods in molecular biol-
                                             chips in the university’s MicroArray Core    the researchers can determine which
ogy generally work on a tedious one-
                                             Facility, which houses complete gene         genes are turned on and to what de-
gene-in-one-experiment basis, which
                                             chip instrumentation. Kuey-Chu Chen,         gree.
does not allow for a whole picture of
                                             a member of the team involved in this           “By using an array containing many
gene function. However, advances in
                                             study, directs this facility.                complementary probes to which a
technology are now paving the way for
                                                To understand how each of these           subject’s tissue is added,” Landfield
biologists to study genes on a much
                                             genes is detected on the chip, we have       says, “we can determine in a single
larger scale.
                                             to dust off some basic terminology from      experiment the expression levels of
   “In the past several years a new tech-
                                             Genetics 101.                                thousands of genes.
nology, called DNA microarray, has
                                                Information about protein structure          “This is the wonderful thing about
revolutionized how we do gene re-
                                             that is encoded into DNA is transcribed      microarrays,” he adds. “They provide
search,” says Philip Landfield, profes-
                                             into complementary (closely related)         us new ways of dealing with complex-
sor and chairman of the Department of
                                             RNA structure. These RNA transcripts         ity because they allow overviews of the
Molecular and Biomedical Pharmacol-
                                             convey this key information from the         simultaneous activity of multiple cellu-
ogy in the UK College of Medicine. An
                                             nucleus to protein-production sites (ri-     lar pathways.”
array, he explains, is an orderly arrange-
                                             bosomes) in other parts of the cell. This
ment of gene probes on a small chip.
                                             RNA becomes a sort of messenger, and         Recently, Landfield’s group has used
“What this new technology allows us to
                                             is aptly called messenger RNA (mRNA).        this technology to better understand
do is measure 20,000 genes simulta-
                                                These mRNA molecules bind natu-           incipient Alzheimer’s. “‘Incipient’
neously and to look at entire genetic
                                             rally and specifically to their comple-      means the very beginning of the dis-
pathways,” he says.
                                             mentary DNA templates, like a key in a       ease regardless of age,” Landfield ex-
   This work starts with what looks like,
                                             lock. A microarray works by exploiting       plains. “This earlier time point is
but isn’t, a simple chip. DNA chips such
                                             this union. The probes on the surface of     extremely vital to study.”
as the human one used in Landfield’s
                                             the chip act like a field of thousands of      And this is where microarrays come
current study, which is focused on bet-
                                             keys, all waiting for the unique locks for   in. This technology recently allowed
ter understanding incipient Alzheimer’s
                                             which they were specifically made.           Landfield and his team to analyze the
disease, are fabricated using a process
                                             When a key fits in a lock, binding oc-       simultaneous activity of multiple cellu-
called photolithography (the same tech-
                                             curs, and it can be detected using laser     lar pathways in the hippocampus of 31

12   Odyssey
                                            Utilizing a new technology called DNA microarray, Philip Landfield (left) and his team,
                                            which includes Kuey-Chu Chen and Eric Blalock, in the UK College of Medicine are
                                            analyzing thousands of genes and genetic pathways to better understand “incipient”
                                            Alzheimer’s—the earliest stage of the disease.

brain samples—22 Alzheimer’s subjects
of varying severity and nine “controls.”
All of these brain samples were ob-
tained through the ADRC’s BRAiNS
program (see sidebar on p. 9).
   An article on this work by lead author
Eric Blalock (pharmacology) appeared
last month in Proceedings of the Na-
tional Academy of Science. In what co-
author Landfield calls “a welcome
comment” on this article, one reviewer
said, “the UK group has convincingly
shown us a new model, in what is the        MMSE was examined and used as a               Landfield says. “It’s very easily confused
largest and best microarray study of        cognitive marker of decline. This test        with normal aging.”
Alzheimer’s disease; the idea of corre-     represents a brief, standardized method          So the researchers ignored whatever
lating gene expression with pathology       by which to “grade” cognitive mental          diagnosis the subject might have had
is unprecedented in this kind of study.”    status. It assesses orientation, attention,   and, instead, used a statistical correla-
Article co-authors included Landfield,      immediate and short-term recall, lan-         tion strategy to define what “incipient”
Jim Geddes (Spinal Cord and Brain           guage, and the ability to follow simple       meant. “We correlated each gene with
Injury Research Center), Chen (phar-        verbal and written commands. It also          how many NFTs there were, and we did
macology), Nada Porter (pharmacol-          provides a total score that places the        the same for the cognitive scores,” says
ogy), and Markesbery.                       individual on a scale of cognitive func-      Blalock, who did the number crunch-
   Two basic indicators of Alzheimer’s      tion. The researchers therefore had two       ing in the office next to Landfield’s.
disease were initially examined in this     ways to quantify the severity of              “We subsequently identified thousands
study: neurofibrillary tangles (NFTs) in    Alzheimer’s-related dysfunction in each       of genes that correlated with one or the
the hippocampus and scores on the           subject: mental decline as measured           other marker in all 31 subjects.”
standard MiniMental Status Examina-         with the MMSE and pathological                    “But the most important thing to
tion (MMSE). All of the brain samples       changes in the brain as measured by           come out of this is that we also identi-
had previously been characterized by        NFT.                                          fied hundreds of genes that correlated
Markesbery, Geddes and other collabo-           “The reason we took this strategy         with the early phase of Alzheimer’s,”
rators, who routinely do brain autop-       instead of initially putting the known        Landfield says. “We were then able to
sies at Sanders-Brown, to determine         Alzheimer’s subjects into groups (in-         assign identified genes to biological
brain pathology. NFT density was given      cipient, moderate or severe) versus the       process categories to get an idea of
a “score” in order to quantify the amount   control group is—and I can’t empha-           which cellular pathways were being
and type of brain deterioration.            size this enough—it’s hard to tell when       turned on.” One important discovery
   Second, each subject’s record on the     someone has incipient Alzheimer’s,”           the group made was that incipient

                                                                                          U n i v e r s i t y o f K e n t u c k y 13
                                                                                             A healthy neuron (top right) contrasted with
                                                                                             a damaged neuron (note its shriveled state
                                                                                             and the presence around the nucleus
                                                                                             of neurofibrillary tangles)

Alzheimer’s is what Landfield calls “a
genomically orchestrated phenom-
   “Researchers knew some genes were
turned on or off, but this is the first study
to find hundreds of these genes that
correlated with incipient Alzheimer’s.”
   “We’ve now defined pathways that
are activated or repressed, and this
knowledge can become a tool to diag-
nose—and predict—who’s going to
develop incipient Alzheimer’s disease,”
Blalock says. Landfield emphasizes the                                                                      Tom Dolan, UK medical illustrator

fact that in order to make such a diag-
nosis, scientists wouldn’t need much               “The ultimate goal,” says Landfield,      January.
tissue. “Brain biopsy is a possibility,” he     “is to intervene earlier so that we can         Schmitt and Wes Ashford (now at
says. “It’s done in some brain cancer           slow the progression of this terrible dis-   Stanford University), working through
patients.”                                      ease, or possibly stop it in its tracks.”    Sanders-Brown and the ADRC, headed
    “Another possibility,” Blalock says,                                                     up UK’s part of a large, multi-center
“is a blood test. White blood cells and                                                      clinical study of memantine, which was
specialized brain cells called microglia
                                                Now on the Market:                           shown to suppress the activity of a key
have a lot in common. Certainly some
                                                The First Drug Shown                         brain chemical involved in mental de-
of the signals that we are measuring in         to Slow Alzheimer's                          terioration. The results of the study,
our study could have originated from            A new drug on the market may be              which was funded by the drug’s Ger-
microglia. If these signaling pathways          excellent news for people with mild to       man manufacturer, Merz Pharmaceuti-
are activated in parallel in the brain          severe Alzheimer’s disease and their         cals, and the National Institute of Aging,
and blood of Alzheimer’s patients, then         families, says Frederick Schmitt, a pro-     were published in The New England
a diagnosis could be made using                 fessor with the UK Department of Neu-        Journal of Medicine in April 2003.
microarray-based blood tests.”                  rology and Sanders-Brown Center on              The study involved 32 medical cen-
   “Of particular importance, these genes       Aging. The drug, memantine (brand            ters nationwide and enrolled 252 pa-
and genetic pathways can now become             name Namenda™), is the first medica-         tients who lived independently. All had
targets for new drugs,” Landfield adds.         tion approved in the United States to        difficulty with daily activities, but could
“We hope that, by using these kinds of          treat moderate to severe Alzheimer’s         still speak and walk. During the 28-
genetic markers and patterns, it’ll be-         disease. Namenda™ was given the FDA          week study, patients received either
come much easier for pharmaceutical             stamp of approval last October and has       memantine or a placebo twice a day.
researchers to develop these drugs.             been available by prescription since         Neither the patients nor their physicians

14    Odyssey
Memantine (Namenda™) is
the first medication approved
in the United States to treat moderate
to severe Alzheimer’s disease. Namenda™
was given the FDA stamp of approval
last October and has been available
by prescription since January.

knew which pill they received. Behav-       per (UK neurology, Sanders-Brown Cen-        memantine story, see sidebar on next
ioral, cognitive and functional tests       ter on Aging, and Lexington Clinic) are      page.]
were used to evaluate patients through-     now under way to determine whether              Is memantine the wonder drug
out the study.                              this drug or a similar drug known as         everyone’s been looking for?
   Overall, the study found that the pa-    neramexane will help these patients.            “We need to stress that although this
tients who were taking memantine               Memantine blocks the activity of a        is a wonderful scientific finding, it isn’t
showed significantly less deterioration     brain chemical called glutamate, which       a cure,” Schmitt says. “It’s another step
in cognition and ability to perform daily   excites neurons, Schmitt explains. “In       in treating a very complex disease.”
life activities.                            the past few years, we’ve learned that
   “These patients seem to be declining     when neurons become over-stimulated
much less, about half as much as ordi-      because of excess glutamate, the nerve
narily expected, over a six-month pe-       cells can become damaged or they can
riod,” says Barry Reisberg, a professor     die. Neurons are literally excited to
of psychiatry at New York University        death.” Many brain cells that respond
School of Medicine, who led the study.      to glutamate are involved in memory
“This medication will slow down the         and learning.
otherwise inexorable progress of this          One reason for doing clinical trials
disease, and it is remarkably free of       such as this one is obviously to further
side effects.” A few patients did report    medical knowledge and hope that it
dizziness, confusion, headache, and         translates into effective drug develop-
constipation.                               ment, Schmitt says. But he says there is
   “Although this drug stabilizes and       another important motivation.                For more
slows progression, brain cells are still       “It allows you to spend more time         information
dying,” Schmitt says. “However,             with patients than might be possible in      about Alzheimer’s
memantine may result in delaying nurs-      a typical busy clinical practice. In these   disease clinical trials
ing home placement by six months to a       studies, patients get quality care from a    at the UK Sanders-
                                                                                         Brown Center on Aging,
year or longer. We now are looking at       whole team—researchers, physicians,
                                                                                         call 859/323-6729
this drug for early Alzheimer’s disease.”   a social worker, and a nurse,” Schmitt       or visit
Studies led by Schmitt and Greg Coo-        says. [For one patient’s personal  
                                                                                         U n i v e r s i t y o f K e n t u c k y 15
Ruth Hobbs (left) with her daughter DeEtta Blackwell was a
participant in a national clinical trial of memantine, a drug to
treat memory loss. Says Ruth today: “I’m delighted about how
I’m doing. I can do anything I want to do really. I’m sure a
happier person than before they started giving me this drug.”

16   Odyssey
Memantine User Says UK Study Has Changed Her Life
T     his was Ruth Hobbs on Thanksgiv-
     ing Day 2002. For the first time, she
hadn’t cooked Thanksgiving dinner for
                                             tient nor the physician knew whether
                                             patients were getting memantine or a
                                             placebo. After six months, all patients
                                                                                           was hospitalized for four days. DeEtta
                                                                                           and other family members noticed that
                                                                                           Ruth slipped mentally by the time she
her family or even had a hand in the         enrolled in the study were given              returned home, and they worried that
cooking. For an hour, she sat alone in       memantine.                                    it was the beginning of another de-
a corner, speaking to no one. When              “We still don’t know what Mom was          cline.
she finally did say something, it was to     getting the first six months, but after she      “It took her four months, but she is
her daughter, DeEtta. Ruth, 73, wanted       started taking memantine at the six-          almost back to where she was before
to know, for the fifth time that day,        month point, she got noticeably better        getting pneumonia,” DeEtta says. “I
when they were leaving to see the doc-       nearly overnight,” DeEtta says. “We           know that without the memantine she
tor.                                         couldn’t believe the difference.”             wouldn’t have come back. She
   “Around this time, Mom would call            Ruth went back to cooking family           wouldn’t be herself any more. She
me six to eight times a day at work. She     dinners and going to church with her          would have lost her independence.”
wanted to go to the doctor every other       son. Now she sews, cleans and arranges           DeEtta gives high marks to the Sand-
day. The day after Thanksgiving din-         silk flowers. And she continues to live       ers-Brown team she and her mother
ner, she didn’t even know it had hap-        independently in a green-roofed cot-          have worked with during and after the
pened. The quality of her life and           tage surrounded by flower beds she            clinical trial.
well-being was horrible,” DeEtta             tends regularly.                                 “It may sound strange to say this, but
Blackwell says.                                 “The memantine has dramatically            I feel like we have our own private care
   Soon after, Ruth was diagnosed with       changed her life,” DeEtta says. “Her          team for Alzheimer’s.” The team in-
Alzheimer’s. “I never felt so hopeless in    sense of well-being is back, she makes        cluded Frederick Schmitt, UK profes-
my life when we got that diagnosis,”         notes and keeps a calendar to help her        sor of neurology, Cooper, Ashleigh
DeEtta says. “I’m a nurse, and I knew        remember upcoming events.”                    Lucas, study coordinator at the Lexing-
very well what it meant.”                       DeEtta was especially impressed            ton Clinic, and Marie Smart, clinical
   Then DeEtta learned about a new           when, four months ago, her mother read        associate, Alzheimer’s Disease Re-
UK study of the drug memantine, used         about a program on KET about                  search Center. “I can trust Momma in
in Germany for more than 20 years for        Alzheimer’s, made a note to see it, and       their hands, and now I don’t have to
general neurological disorders and           then remembered to watch the pro-             stay glued to the Internet looking for
approved in 2002 for use in Alzheimer’s      gram. “I’d forgotten it was on myself,        every new book out there on
patients throughout Europe. “When Dr.        but Mom didn’t,” DeEtta says. “I had          Alzheimer’s. It’s because of them that
[Greg] Cooper told me about this, I          mixed feelings about her seeing it, but       Momma is in her own house right now.”
asked Momma if she’d like to join the        it’s something she wanted to do.”                This is Ruth Hobbs today: “I’m de-
study. ‘Sure,’ she said. ‘If I do have          After watching the program, Ruth           lighted about how I’m doing. I can do
Alzheimer’s, what have I got to lose?’”      called her daughter. “God, DeEtta, I’m        anything I want to do really. I’m sure a
Cooper is an assistant professor at UK’s     so glad they’re giving me this pill. With-    happier person than before they started
Sanders-Brown Center on Aging and            out it, I’d be just like those people on      giving me this drug. I was starting to get
head of the neurology section of the         TV.”                                          depressed.
center’s memory disorders outreach              “This was really touching, I thought,”        “I live by myself and live a happy,
clinic.                                      DeEtta says.                                  normal life.”
   The first six months of the study were       Ruth developed severe pneumonia
“blind,” meaning that neither the pa-        during the 2003 Christmas holidays and

                                                                                           U n i v e r s i t y o f K e n t u c k y 17

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