126 - Download Now PDF - PDF

Document Sample
126 - Download Now PDF - PDF Powered By Docstoc
					American Journal of Alzheimer's Disease and
           Other Dementias®
                                                http://aja.sagepub.com



    Antioxidant protection and neurodegenerative disease: The role of amyloid-ß and tau
                    Rudy J. Castellani, Hyoung-gon Lee, George Perry and Mark A. Smith
                             Am J Alzheimers Dis Other Demen 2006; 21; 126
                                    DOI: 10.1177/153331750602100213

                                The online version of this article can be found at:
                              http://aja.sagepub.com/cgi/content/abstract/21/2/126


                                                            Published by:

                                            http://www.sagepublications.com




 Additional services and information for American Journal of Alzheimer's Disease and Other Dementias® can be found at:

                                      Email Alerts: http://aja.sagepub.com/cgi/alerts

                                   Subscriptions: http://aja.sagepub.com/subscriptions

                                  Reprints: http://www.sagepub.com/journalsReprints.nav

                              Permissions: http://www.sagepub.com/journalsPermissions.nav

                                 Citations http://aja.sagepub.com/cgi/content/refs/21/2/126




                                             Downloaded from http://aja.sagepub.com by on May 12, 2010
      Antioxidant protection and neurodegenerative
                 disease: The role of amyloid-f3 and                                                                      tau
                                                 Rudy J. Castellani, MD
                                                 Hyoung-gon Lee, PhD
                                                   George Perry, PhD
                                                  Mark A. Smith, PhD




Abstract                                                                           Key words. Alzheimer k disease, amyloid-f3, antioxidant,
                                                                                free radical, phosphorylation, redox-active metals, tau
   In Alzheimer s disease (AD), the major components of
senile plaques and neurofibrillary tangles, amyloid-f3                           Introduction
and tau, respectively, are thought by many to play a key
role in disease initiation and progression. However,                               Amyloid-f3 and the low molecular weight micro-
herein we propose that rather than being initiators of                          tubule-associate protein tau are the best studied proteins
disease pathogenesis, the lesions that characterize AD,                         relating to the pathogenesis of Alzheimer's disease
senile plaques and neurofibrillary pathology, occur con-                        (AD). Although not surprising, because the pathological
sequent to oxidative stress and, importantly, function as                       diagnosis of AD is dependent upon the quantity of amy-
a primary line of antioxidant defense. Importantly, this                        loid-P and tau depositions,1 2 the amalgamation of diag-
paradigm shift in thinking about the role of lesions in                         nostic and mechanistic views relating to the disease may
disease also provides an explanation for the appearance                         be misleading. It is important to recognize that the patho-
of both amyloid-/3 and tau in control individuals given                         logical diagnosis of AD brains merely represents the
the increased levels of oxidative stress associated with                        association of a pattern of pathological changes with a
the aged brain. In AD, oxidative stress is not only high                        clinical disease state, or a clinicopathological associa-
but chronic and is superimposed upon an age-related                             tion. Amyloid-3 and tau are crucial proteins that are
vulnerable environment. Therefore, one wouldpredict,                            exploited for diagnostic purposes; however, lesions that
successfully, an increased lesion load in patients with                         encompass these proteins, as with lesions of all neurode-
AD above and beyond that seen in normal aging. The                              generative diseases, do not by themselves indicate etiol-
notion that amyloid-f3 and tau accumulations indicate                           ogy. We believe, as we discuss below, their mechanistic
adaptation and, likely, physiological processes sheds                           importance has far less to do with their consequences (a
light on the pathological expression ofdisease and calls                        presumption) tha'n with the factors that led to their for-
into question the rationale of current therapeutic efforts                      mation. Thus, the goal of this review is to present an
targeted toward lesion removal.                                                 alternative hypothesis for the role of amyloid-f3 and tau
                                                                                deposition in this disease.
Rudy J. Castellani, MD, Department of Pathology, University of
Maryland, Baltimore, Maryland                                                   Amyloid-f3
Hyoung-gon Lee, PhD, Department of Pathology, Case Western
Reserve University, Cleveland, Ohio.                                               The prevailing view concerning the pathogenesis of
George Perry, PhD, Department ofPathology, Case Western Reserve                 AD is that amyloid-P causes the disease.3 Evidence to
University, Cleveland, Ohio.                                                    support this contention is based on genetic data and, to a
Mark A. Smith, PhD, Department of Pathology, Case Western                       lesser extent, clinicopathological data. First, mutations
Reserve University Cleveland, Ohio.                                             in the gene for APPP lead to familial, early-onset AD

126                                                                                     American Journal ofAlzheimer's Disease and Other Dementias
                                                                                                            Volume 21, Number 2, March/April 2006
                                                Downloaded from http://aja.sagepub.com by on May 12, 2010
(autsomal dominant). Second, patients with Down's syn-                           better predictor of the disease.24 Specifically, SDS-stable
drome, and therefore an extra copy of the Aj3PP gene,                            oligomers, and not monomers, of this form of amyloid-f3
consistently develop AD changes, typically by the fifth                          seem to play an important role, as shown by augmented
decade of life.4 Third, amyloid-fP deposits are increased                        presence of these oligomers during the expression of
in the AD brain and correlate somewhat with disease                              mutations in APPP or presenilin,25 as well as by their
severity.5 On the other hand, families carrying AiPP                             capacity to inhibit neuronal plasticity parameters in vivo
mutations are exceedingly rare, and it remains to be                             when microinjected into the brains of rodents.26'27
determined whether these kindreds are only tangentially                              Conversely, amyloid-3 is not always present in the
representative of sporadic AD. Similarly, the genetic                            brains of cognitively normal elderly. This might be
aberration in Down's syndrome clearly leads to a "cas-                           explained simply on the basis of genetic heterogeneity-
cade" of pathophysiology over and above AP deposits                              that, for reasons that remain to be elucidated, some indi-
and may also relate only tangentially to sporadic AD.                            viduals have efficient endogenous antioxidant defense
Moreover, even if representative, the notion of AP3                              systems and thus age more effectively or less pathologi-
deposits per se as neurotoxic lesions may be called into                         cally. Alternatively, such individuals may have supple-
question6 in light of the early appearance of sequelae of                        mented their diets with antioxidants throughout their
oxidative stress relative to AP3 deposits,7,8 whereas the                        lifespan, compensating for age-related declines in
concept of AP deposits as protective or adaptive phe-                            antioxidant defenses.28-3 If amyloid-f3 and intracellular
nomena makes mechanistic sense in both familial auto-                            neurofibrillary tangles (NFT) deposition provides an
somal dominant and sporadic AD.                                                  antioxidant function, it is likely that these processes will
   Neurons respond to oxidative stress, both in vitro and                        be recruited during times when oxidative stress is high
in vivo, by increasing amyloid-P production,9'11 and this                        and the endogenous antioxidant defenses are compro-
increased amyloid-f is associated with a consequent                              mised. Nevertheless, if these systems remain relatively
reduction in oxidative stress.7'8 Proteins, such as amy-                         efficient or are supported by exogenous antioxidant sup-
loid-f3, that are induced under oxidative conditions and                         plementation, the antioxidant effects of amyloid-f and
act to lessen oxidative damage are typically thought of as                       NFT, and therefore deposits, may not be necessary.
antioxidants, and, in this regard, we recently demonstrat-                       Preliminary data from in vitro studies support this
ed that amyloid-P is a bona fide antioxidant that can act                        hypothesis. Incubation of primary cortical neurons with
as a potent superoxide dismutase.'2 By this logic, AD                            extract from blueberry, a fruit rich in antioxidants,28-31
kindreds with Af3PP mutations lose, by virtue of muta-                           prevents tau phosphorylation when neurons are present-
tion, effective antioxidant capacity, whereas the prodi-                         ed with oxidative stress insult (Casadesus, Smith, and
gious AB deposits themselves are signatures not of                               Joseph, unpublished data), analogous to the effects of
neurotoxicity per se but of oxidative imbalance and an                           endogenous antioxidants.32'33
oxidative stress response. This is consistent with the data                          Moreover, unbiased stereological counting indicates
that virtually everyone over the age of 40 years has                             that during normal aging there may be little or no cell
detectable amyloid-f deposits, an age, not coincidental-                         loss, despite, as pointed out above, the presence of an
ly, when redox alterations are first manifest.8 The alter-                       increasing number of plaques.34 Importantly, even the
nate view, that everyone at midlife is on the verge of                           hyperphysiologic levels of amyloid-P found in engi-
developing AD, is manifestly extreme and not supported                           neered AD transgenic mice35 lead only to senile plaque
by the fact that a large percentage of cognitively intact                        formation in middle-aged mice and are, like their human
aged individuals have AP loads equivalent to those                               counterparts, preceded by oxidative stress.36-38 Taken
patients with AD. 3                                                              together, these findings indicate that amyloid-, is not dri-
    Fibrillar or aggregated forms of amyloid-f3, like those                      ving the pathogenic process, but rather is a consequence of
present in the senile plaques, are toxic to cultured neurons                     the pathogenesis that serves an antioxidant function.
in vitro by inducing oxidative stress.'4-'7 However, neuro-                          The idea that amyloid-,B is protective should not be
toxicity in cultured cells may also be an artifact of in vitro                   surprising. Neuronal degeneration is associated with a
conditions,'8 an idea further supported by the findings that                     number of responses, including the induction of heat
neither isolated senile plaques nor immobilized amyloid-f                        shock proteins such as heme oxygenase-l 39 and ubiqui-
elicit neurotoxity in vivo or in vitro.'9-21 Thus, the capacity                  tin,40,41 which, like amyloid-p,,show a relationship with
of amyloid-f to induce oxidative stress remains contro-                          cognitive decline However, only amyloid-f is consid-
versial.22 Furthermore, in vivo, the presence and density                        ered pathogenic because amyloid-~is neurotoxic in vitro
of amyloid-J3 correlates weakly with the onset and severi-                       and is associated with neuronal loss in vivo. On the other
ty of AD,23 whereas recent data suggest that the presence                        hand, neurotoxicity in cultured cells may be an artifact of
of the soluble form of amyloid-,B in the brain may be a                          in vitro conditions,'8 an idea further supported by the


American Journal ofAlzheimer's Disease and Other Dementias                                                                               127
Volume 21, Number 2, March/April 2006
                                                Downloaded from http://aja.sagepub.com by on May 12, 2010
findings that neither isolated senile plaques nor immobi-                        decades.53 Intriguingly, although cytoskeletal proteins
lized amyloid-f elicit neurotoxity in vivo or in vitro."19-2                     such as tau and neurofilaments have a long half-life, the
Thus, the capacity of amyloid-f to induce oxidative                              same extent of carbonyl modification is found through-
stress remains controversial.22 Recent data suggest that                         out the normal aging process as well as along the length
the oxidant properties of amyloid-f may stem from its                            of the axon.54 This suggests that the oxidative modifica-
capacity to interact with transition metals and mediate                          tion of cytoskeletal proteins is under tight regulation.
toxicity via redox-active ions, which precipitate lipid                             Both tau and neurofilament protein appear uniquely
peroxidation and cellular oxidative stress.'8                                    adapted to oxidative attack due to theirhigh content of
   The few reports demonstrating neuronal loss in some                           lysine-serine-proline domains. Exposure of these
transgenic mice with amyloid-f deposits42 argue that                            domains on the protein surface is effected by extensive
amyloid-f3 is a bioactive substance, but we believe that                        phosphorylation of serine residues resulting in an oxida-
these reports fall short of providing a compelling analo-                       tive sponge of surface-modifiable lysine residues.54
gy to sporadic AD in humans. Moreover, there is little                          Because phosphorylation plays this pivotal role in redox
evidence demonstrating behavioral deficits in mice                              balance, it is not surprising that oxidative stress, through
transgenic for only APPP mutations. The most consistent                         activation of MAP kinase pathways, leads to phosphory-
deficits have been shown in mice transgenic for more than                       lation,55-58 nor that conditions associated with chronic
one mutation, e.g., APPP/PS 11,44 and even then the                             oxidant stress, such as AD, are invariably associated
deficits are superimposed upon an aged environment.                             with extensive phosphorylation ofcytoskeletal elements.
   Finally, the relationship between Aj3PP mutations and                        Indeed, other neurological conditions where phosphory-
disease is classically explained as a gain of function                          lated tau and neurofilament protein accumulations occur
process whereby aberrant APPP leads to increased AP                             also show evidence of oxidative adducts, e.g., corti-
and consequent neurotoxicity/neurodegeneration. We                              cobasal degeneration,59 progressive supranuclear
alternatively suggest that such mutations in a protein that                     palsy,60 and frontal temporal dementia.6' Given this pro-
functions as an antioxidant lead to loss of protection. The                     tective role of tau phosphorylation, it is not surprising
prodigious AP deposits in brain and blood vessels are                          that embryonic neurons that survive treatment with oxi-
thus the pathological signatures of the loss of function                        dants have more phospho-tau immunoreactivity relative
and reflect an altered steady state as a result of the muta-                   to those that die.62 Further, since heme oxygenase induc-
tion. With this paradigm in mind, it is not surprising that                    tion and tau expression are opposing,33'5' the reduced
free radicals are among the best inducers of APPP pro-                         oxidative damage in neurons with tau accumulation
tein expression and consequent amyloid-f3 production.9                         may be a part of the antioxidant function of phosphory-
                                                                               lated tau.
Tau                                                                                The concept that intracellular inclusions are manifes-
                                                                               tations of cell survival has recently found support in a
    The notion of accumulating proteins in AD as signa-                        Huntington's disease model.63 In this neuronal model,
tures of oxidative imbalance is not restricted to amyloid-                     cell death was mutant-huntingtin-dose- and polygluta-
P and applies equally well to tau.8 The accumulation of                        mine-dependent; however, huntingtin inclusion forma-
phosphorylated tau as NFT in neurons, according to                             tion correlated with cell survival. Thus, in this model, as
recent data, is an analogous protective antioxidant                            in AD, inclusion formation represents adaptation, or a
response because quantitative analysis of the extent of                        productive, beneficial response to the otherwise neu-
oxidative damage in AD shows that the oxidative dam-                           rodegenerative process. Taken together with our studies,
age is reduced in those neurons with the most                                  this represents a fundamental and necessary change in
cytopathology.8 For example, some studies suggest that                         which pathological manifestations of neurodegenerative
most neuronal loss in AD occurs prior to NFT deposi-                           disease are interpreted.
tion45'46 which, interestingly, is a period that is associated
with high levels of oxidative stress, whereas subsequent                       Summary
deposition of NFT decreases these levels.47
   Consistent with this view is the physiological modifica-                       Although both amyloid-, and tau are essentially asso-
tion of tau and neurofilament proteins by lipid peroxidation                   ciated with etiology by various laboratories, the
products and carbonyls.48'49 Indeed, oxidative stress and                      observed decrease in oxidative damage with amyloid-j3
attendant modification of tau by products of oxidative                         and tau accumulation suggests, rather, a mechanism of
stress including 4-hydroxy-2-nonenal5°'5' as well as                           survival.6,43,6368 Moreover, as a consequence of age-
other cytotoxic carbonyls,52 though leading to protein                         related oxidative stress, there is an upregulation of phos-
aggregation as NFT, enable such neurons to survive for                         phorylated tau and amyloid-,B that resultin NFT and

128                                                                                    American Journal of Alzheimer's Disease and Other Dementias
                                                                                                            Volume 21, Number 2, March/April 2006
                                               Downloaded from http://aja.sagepub.com by on May 12, 2010
senile plaques, respectively. Both lesions serve antioxi-                             toxicity of synthetic beta-amyloid protein in hippocampal cultures.
dant functions and limit age-related neuronal dysfunc-                                Eur JPharmacol. 1991; 207: 367-368.
                                                                                      15. Huang X, Cuajungco MP, Atwood CS, et al.: Cu(II) potentiation
tion. However, in AD, this age-related oxidative stress is                            of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen
compounded by metabolic49 and metallic5'152 sources of                                peroxide production and metal reduction. JBiol Chem. 1999; 274:
oxidant stress that, despite greatly enhancing amyloid-4                              371 1l-37116.
production and tau phosphorylation, lead to neurodegen-                               16. Boyd-Kimball D, Sultana R, Abdul HM, et al.: Gamma-glutamyl-
eration and consequent dementia. In light of these obser-                             cysteine ethyl ester-induced up-regulation of glutathione protects
vations, efforts aimed solely at eliminating amyloid-4                                neurons against Abeta( I -42)-mediated oxidative stress and neurotox-
                                                                                      icity: Implications for Alzheimer's disease. JNeurosci Res. 2005; 79:
appear short-sighted.                                                                 700-706.
                                                                                      17. Boyd-Kimball D, Sultana R, Poon HF, et al.: Gamma-glutamyl-
Acknowledgments                                                                       cysteine ethyl ester protection of proteins from Abeta( 1-42)-mediated
    Work in the authors 'laboratories is supported by the National                    oxidative stress in neuronal cell culture: A proteomics approach. J
Institutes of Health, the Alzheimer s Association, the John Douglas                   Neurosci Res. 2005; 79: 707-713.
French Alzheimer Foundation, and Philip Morris USA Inc. and                           18. Rottkamp CA, Raina AK, Zhu X, et al.: Redox-active iron medi-
Philip Morris International.                                                          ates amyloid-beta toxicity. Free Radic Biol Med. 2001; 30: 447-450.
                                                                                      19. Frautschy SA, Cole GM, Baird A: Phagocytosis and deposition of
                                                                                      vascular beta-amyloid in rat brains injected with Alzheimer beta-
References                                                                            amyloid.AmrJPathol. 1992; 140: 1389-1399.
                                                                                      20. Canning DR, McKeon RJ, DeWitt DA, et al.: Beta-amyloid of
1. Braak H, Braak E: Neuropathological stageing ofAlzheimer-relat-                    Alzheimer's disease induces reactive gliosis that inhibits axonal out-
ed changes. Acta Neuropathol (Berl). 1991; 82: 239-259.                               growth. Exp Neurol. 1993; 124: 289-298.
2. Mirra SS, Heyman A, McKeel D, et al.: The Consortium to                            21. DeWitt DA, Perry G, Cohen M, et al.: Astrocytes regulate
Establish a Registry for Alzheimer's Disease (CERAD). Part 1IL                        microglial phagocytosis of senile plaque cores of Alzheimer's dis-
Standardization of the neuropathologic assessment of Alzheimer's                      ease. Exp Neurol. 1998; 149: 329-340.
disease. Neurology. 1991; 41: 479-486.                                                22. Walter MF, Mason P, Mason RP: Alzheimer's disease amyloid
3. Selkoe DJ: Alzheimer's disease results from the cerebral accumu-                   beta peptide 25-35 inhibits lipid peroxidation as a result of its mem-
lation and cytotoxicity of amyloid beta-protein. JAlzheimers Dis.                     brane interactions. Biochem Biophys Res Commun. 1997; 233: 760-
2001; 3: 75-80.                                                                       764.
4. Roizen NJ, Patterson D: Down's syndrome. Lancet. 2003; 361:                        23. Davies L, Wolska B, Hilbich C, et al.: A4 amyloid protein deposi-
1281-1289.                                                                            tion and the diagnosis of Alzheimer's disease: Prevalence in aged
5. Knowles RB, Gomez-Isla T, Hyman BT: Abeta associated neuropil                      brains determined by immunocytochemistry compared with conven-
changes: Correlation with neuronal loss and dementia. JNeuropathol                    tional neuropathologic techniques. Neurology. 1988; 38: 1688-1693.
Exp Neurol. 1998; 57: 1122-1130.                                                      24. McLean CA, Cherny RA, Fraser FW, et al.: Soluble pool of Abeta
6. Smith MA, Joseph JA, Perry G: Arson. Tracking the culprit in                       amyloid as a determinant of severity of neurodegeneration in
Alzheimer's disease. Ann N YAcadSci. 2000; 924: 3 5-38.                               Alzheimer's disease. Ann Neurol. 1999; 46: 860-866.
7. Nunomura A, Perry G, Pappolla MA, et al.: Neuronal oxidative                       25. Xia W, Zhang J, Kholodenko D, et al.: Enhanced production and
stress precedes amyloid-beta deposition in Down syndrome. J                           oligomerization of the 42-residue amyloid beta-protein by Chinese
Neuropathol Exp Neurol. 2000; 59: 1011-1017.                                          hamster ovary cells stably expressing mutant presenilins. J Biol
8. Nunomura A, Perry G. Aliev G; et al.: Oxidative damage is the ear-                 Chem. 1997; 272: 7977-7982.
liest event in Alzheimer disease. JNeuropathol Exp Neurol. 2001; 60:                  26. Walsh DM, Klyubin 1, Fadeeva JV, et al.: Naturally secreted
759-767.                                                                              oligomers of amyloid beta protein potently inhibit hippocampal long-
9. Yan SD, Yan SF, Chen X, et al.: Non-enzymatically glycated tau in                  term potentiation in vivo. Nature. 2002; 416: 535-539.
Alzheimer's disease induces neuronal oxidant stress resulting in                      27. Walsh DM, Townsend M, Podlisny MB, et al.: Certain inhibitors
cytokine gene expression and release of amyloid beta-peptide. Nat                     of synthetic amyloid beta-peptide (Abeta) fibrillogenesis, block
Med. 1995; 1: 693-699.                                                                oligomerization of natural Abeta and thereby rescue long-term poten-
10. Tamagno E, Parola M, Bardini P, et al.: Beta-site APP cleaving                    tiation. JNeurosci. 2005; 25: 2455-2462.
enzyme up-regulation induced by 4-hydroxynonenal is mediated by                       28. Joseph JA, Shukitt-Hale B, Denisova NA, et al.: Long-term
stress-activated protein kinases pathways. JNeurochem. 2005; 92:                      dietary strawberry, spinach, or vitamin E supplementation retards the
628-636.                                                                              onset of age-related neuronal signal-transduction and cognitive
 1 1. van Groen T, Puurunen K, Maki HM, et al.: Transformation of dif-                behavioral deficits. JNeurosci. 1998; 18: 8047-8055.
fuse beta-amyloid precursor protein and beta-amyloid deposits to                      29. Joseph JA, Shukitt-Hale B, Denisova NA, et al.: Reversals of age-
plaques in the thalamus after transient occlusion of the middle cere-                 related declines in neuronal signal transduction, cognitive, and motor
bral artery in rats. Stroke. 2005; 36: 1551-1556.                                     behavioral deficits with blueberry, spinach, or strawberry dietary sup-
12. Cuajungco MP, Goldstein LE, NunomuraA, et al.: Evidence that                      plementation. JNeurosci. 1999; 19: 8114-812 1.
the beta-amyloid plaques of Alzheimer's disease represent the redox-                  30. Bickford PC, Gould T, BriederickL, et al.: Antioxidant-rich diets
silencing and entombment of abeta by zinc. JBiol Chem. 2000; 275:                     improve cerebellar physiology and motor learning in aged rats. Brain
 19439- 19442.                                                                        Res. 2000; 866: 211-217.
 13. Davis DG, Schmitt FA, Wekstein DR, et al.: Alzheimer neu-                        31. Casadesus G, Shukitt-Hale B, Stellwagen HM, et al.: Modulation
ropathologic alterations in aged cognitively normal subjects. J                       of hippocampal plasticity and cognitive behavior by short-term blue-
Neuropathol Exp Neurol. 1999; 5 8: 3 76-3 8 8.                                        berry supplementation in aged rats. Nutr Neurosci. 2004; 7: 309-316.
 14. Pike CJ, Walencewicz AJ, Glabe CG, et al.: Aggregation-related                   32. Lee HG, Perry G, Moreira Pi, et al.: Tau phosphorylation in


American Journal ofAlzheimer's Disease and Other Dementias                                                                                               129
Volume 21, Number 2, March/April 2006
                                                     Downloaded from http://aja.sagepub.com by on May 12, 2010
 Alzheimer's disease: Pathogen or protector? Trends Mol Med. 2005;                     Biol Med. 2005; 3 8: 746-754.
 11: 164-169.                                                                           51. Takeda A, Smith MA, Avila J, et al.: In Alzheimer's disease, heme
 33. Takeda A, Perry G. Abraham NQG et al.: Overexpression of heme                     oxygenase is coincident with Alz5O, an epitope of tau induced by 4-
 oxygenase in neuronal cells, the possible interaction with Tau. JBiol                 hydroxy-2-nonenal modification. J Neurochem. 2000; 75: 1234-
 Chem. 2000; 275: 5395-5399.                                                            1241.
 34. Long JM, Mouton PR, Jucker M et al.: What counts in brain                         52. Calingasan NY, Uchida K, Gibson GE: Protein-bound acrolein: A
 aging? Design-based stereological analysis of cell number. J                          novel marker of oxidative stress in Alzheimer's disease. J
 Gerontol A Biol Sci Med Sci. 1999; 54: B407-41 7.                                     Neurochem. 1999; 72: 751-756.
 35. Hsiao K, Chapman P, Nilsen S, et al.: Correlative memory                          53. Morsch R, Simon W, Coleman PD: Neurons may live for decades
deficits, Abeta elevation, -and amyloid plaques in transgenic mice.                    with neurofibrillary tangles. JNeuropathol Exp Neurol. 1999; 58:
Science. 1996; 274: 99-102.                                                             188-197.
36. Pappolla MA, Chyan YJ, Omar RA, et al.: Evidence of oxidative                      54. Wataya T, Nunomura A, Smith MA, et al.: High molecular weight
stress and in vivo neurotoxicity of beta-amyloid in a transgenic                       neurofilament proteins are physiological substrates of adduction by
mouse model ofAlzheimer's disease: A chronic oxidative paradigm                        the lipid peroxidation product hydroxynonenal. JBiol Chem. 2002;
for testing antioxidant therapies in vivo. Am J Pathol. 1998; 152:                     277: 4644-4648.
87 1-877.                                                                              55. Zhu X, Rottkamp CA, Boux H, et al.: Activation of p38 kinase
37. Smith MA, Hirai K, Hsiao K, et al.: Amyloid-beta deposition in                     links tau phosphorylation, oxidative stress, and cell cycle-related
Alzheimer transgenic mice is associated with oxidative stress. J                       events in Alzheimer disease. JNeuropathol Exp Neurol. 2000; 59:
Neurochem. 1998; 70: 2212-2215.                                                        880-888.
38. Pratico D, Uryu K, Leight S, et al.: Increased lipid peroxidation                  56. Zhu X, Rottkamp CA, Hartzler A, et al.: Activation of MKK6, an
precedes amyloid plaque formation in an animal model of Alzheimer                      upstream activator of p38, in Alzheimer's disease. JNeurochem.
amyloidosis. JNeurosci. 2001; 21: 4183-4187.                                           200 1; 79: 311-318.
39. Smith MA, Kutty RK, Richey PL, et al.: Heme oxygenase-1 is                         57. Zhu X, Castellani RJ, Takeda A, et al.: Differential activation of
associated with the neurofibrillary pathology of Alzheimer's disease.                  neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: The 'two
Am JPathol. 1994; 145: 42-47.                                                          hit' hypothesis. MechAgeingDev. 2001; 123: 39-46.
40. Mori H, Kondo J, Ihara Y: Ubiquitin is a component ofpaired helical                58. Zhu X, Raina AK, Rottkamp CA, et al.: Activation and redistribu-
filaments inAlzheimer's disease. Science. 1987; 235: 1641-1644.                        tion of c-jun N-terminal kinase/stress activated protein kinase in
41. Perry G. Friedman R, Shaw G. et al.: Ubiquitin is detected in neu-                 degenerating neurons in Alzheimer's disease. JNeurochem. 2001;
rofibrillary tangles and senile plaque neurites of Alzheimer disease                   76: 435-441.
brains. ProcNatlAcadSci USA. 1987; 84: 3033-3036.                                      59. Castellani R, Smith MA, Richey PL, et al.: Evidence for oxidative
42. Calhoun ME, Wiederhold KH, Abramowski D, et al.: Neuron loss                       stress in Pick disease and corticobasal degeneration. Brain Res. 1995;
inAPPtransgenic mice. Nature. 1998; 395: 755-756.                                      696: 268-271.
43. Joseph J, Shukitt-Hale B, Denisova NA, et al.: Copernicus revisit-                 60. Odetti P, Garibaldi S, Norese R, et al.: Lipoperoxidation is selec-
ed: amyloid beta inAlzheimer's disease. NeurobiolAging. 2001; 22:                      tively involved in progressive supranuclear palsy. JNeuropathol Exp
13 1-146.                                                                              Neurol. 2000; 59: 393-397.
44. Gordon MN, King DL, Diamond DM, et al.: Correlation between                        61. Gerst JL, Siedlak SL, Nunomura A, et al.: Role of oxidative stress
cognitive deficits and Abeta deposits in transgenic APP+PS 1 mice.                     in frontotemporal dementia. Dement Geriatr Cogn Disord. 1999; 10
Neurobiol Aging. 2001; 22: 3 77-3 85.                                                  Suppl 1: 85-87.
45. Gomez-Isla T, Hollister R, West H, et al.: Neuronal loss correlates                62. Ekinci FJ, Shea TB: Phosphorylation of tau alters its association
with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann                   with the plasma membrane. Cell Mol Neurobiol. 2000; 20: 497-508.
Neurol. 1997; 41: 17-24.                                                               63. Arrasate M, Mitra S, Schweitzer ES, et al.: Inclusion body forma-
46. Kril JJ, Patel S. Harding AJ, et al.: Neuron loss from the hip-                    tion reduces levels of mutant huntingtin and the risk of neuronal
pocampus ofAlzheimer's disease exceeds extracellular neurofibril-                      death. Nature. 2004; 431: 805-8 10.
lary tangle formation. Acta Neuropathol (Berl). 2002; 103: 3 70-376.                   64. Perry G, NunomuraA, Raina AK, et al.: Amyloid-beta junkies.
47. Nunomura A, Perry G, Pappolla MA, et al.: RNA oxidation is a                       Lancet. 2000; 355: 757.
prominent feature of vulnerable neurons in Alzheimer's disease. J                      65. Smith MA, Atwood CS, Joseph JA, et al.: Predicting the failure of
Neurosci. 1999; 19: 1959-1964.                                                         amyloid-beta vaccine. Lancet. 2002; 359: 1864-1865.
48. Smith MA, Rudnicka-Nawrot M, Richey PL, et al.: Carbonyl-                          66. Rottkamp CA, Atwood CS, Joseph JA, et al.: The state versus
related posttranslational modification of neurofilament protein in the                 amyloid-beta: The trial ofthe most wanted criminal in Alzheimer dis-
neurofibrillary pathology of Alzheimer's disease. J Neurochem.                         ease. Peptides. 2002, 23: 1333-1341.
1995; 64: 2660-2666.                                                                   67. Smith MA, Casadesus G. Joseph JA, et al.: Amyloid-beta and tau
49. Sayre LM, Zelasko DA, Harris PL, et al.: 4-Hydroxynonenal-                         serve antioxidant functions in the aging and Alzheimer brain. Free
derived advanced lipid peroxidation end products are increased in                      Radic Biol Med. 2002; 33: 1194-1199.
Alzheimer's disease. J Neurochem. 1997; 68: 2092-2097.                                 68. Lee HQ, Casadesus G. Zhu X, et al.: Challenging the amyloid cas-
50. Liu Q, Smith MA, Avila J, et al.: Alzheimer-specific epitopes of                   cade hypothesis: Senile plaques and amyloid-beta as protective adap-
tau represent lipid peroxidation-induced conformations. Free Radic                     tations to Alzheimer disease. Ann N YAcad Sci. 2004; 1019: 1-4.




130                                                                                             American Journal of Alzheimer's Disease and Other Dementias
                                                                                                                     Volume 2 1, Number 2, March/April 2006
                                                       Downloaded from http://aja.sagepub.com by on May 12, 2010

				
DOCUMENT INFO