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									American Journal of Alzheimer's Disease and
           Other Dementias®

    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

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      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
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(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
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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.
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oxidant stress that, despite greatly enhancing amyloid-4                              371 1l-37116.
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eration and consequent dementia. In light of these obser-                             cysteine ethyl ester-induced up-regulation of glutathione protects
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                                                                                      icity: Implications for Alzheimer's disease. JNeurosci Res. 2005; 79:
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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.
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130                                                                                             American Journal of Alzheimer's Disease and Other Dementias
                                                                                                                     Volume 2 1, Number 2, March/April 2006
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