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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. 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