Sci. Aging Knowl. Environ., 3 May 2006
Vol. 2006, Issue 8, p. pe10
[DOI: 10.1126/sageke.2006.8.pe10]


Neuropathology in Alzheimer's Disease: Awaking from a Hundred-Year-Old Dream

Akihiko Nunomura, Rudy J. Castellani, Hyoung–gon Lee, Paula I. Moreira, Xiongwei Zhu, George Perry, and Mark A. Smith

The authors are in the Department of Psychiatry and Neurology at Asahikawa Medical College, Asahikawa 078–8510, Japan (A.N.), the Department of Pathology (Neuropathology) at the University of Maryland, Baltimore, Maryland 21201, USA (R.J.C.), the Department of Pathology at Case Western Reserve University, Cleveland, Ohio 44106, USA (H.L., P.I.M., X.Z., G.P., and M.A.S.), the Center for Neuroscience and Cell Biology of Coimbra at the University of Coimbra, 3004–517 Coimbra, Portugal (P.I.M.), and the College of Sciences at the University of Texas at San Antonio, San Antonio, Texas 78249, USA (G.P.). E–mail: mark.smith{at} (M.A.S.), nuno{at} (A.N.)

Key Words: Alzheimer's disease • amyloid-beta • neurofibrillary tangle • oxidative stress • senile plaque • tau


One hundred years ago, the German psychiatrist and neuropathologist Alois Alzheimer gave a lecture that made him famous, in which he identified a disease of the cerebral cortex, namely, Alzheimer's disease (AD). In individuals with this condition, the cerebral cortex was thinner than normal, and senile plaques, previously only encountered in elderly people, were found in the brain along with neurofibrillary tangles (NFTs) (1) (see Honig and Chin Case Study). Amyloid-beta (Abeta) and the microtubule-associated protein tau, major constituents of extracellular senile plaques and intraneuronal NFTs, respectively, are among the best studied proteins in all of neurobiology and figure centrally into much of the research dedicated to AD (see "Detangling Alzheimer's Disease"). Although this emphasis is not surprising, as the pathological diagnosis of AD is dependent on the quantity of Abeta and tau deposits within cortical gray matter (2, 3), we suggest that this strict linkage of diagnostic and mechanistic views is misleading, particularly in the case of neurodegenerative disease.

Neuropathological changes in subjects with dementia are, by definition, end-stage phenomena. Although such changes allow case characterization and lend themselves to disease classification and modeling, the lesions themselves are not etiological. They are pathognomonic but not pathogenic. This truth would appear to be self-evident, yet the medical and scientific literature suggests otherwise. It is now customary to view Abeta plaques in AD as primary etiological, neurotoxic lesions, such that by removing them through immunotherapy, clinical improvement may result. The foundation for this line of thinking lies in the existence of rare kindreds (in which individuals are at high risk for developing AD) with mutations in Abeta, or mutations believed to affect the processing of Abeta, and then the extrapolation of concepts relevant to the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to the onset and progression of sporadic disease. In this Perspective, we present an alternative hypothesis for the role of Abeta and tau deposition in AD that may herald a paradigm shift in our views of neurodegenerative diseases.


The scientific literature as well as popular media accounts are replete with the fundamental concept that Abeta causes disease (4). Genetic data are often suggested as a priori evidence of this "fact" because amyloid-beta protein precursor (APP) mutations lead to early-onset autosomal-dominant AD, and because patients with Down syndrome, who carry an extra copy of the APP gene, consistently develop AD-like changes with prolonged survival (see Devenny Case Study). Clinicopathological data may also be cited, because Abeta deposits are increased in the AD brain compared with the normal brain (5). On the other hand, AD kindreds with APP mutations are exceedingly rare, and it remains to be determined whether these kindreds are only tangentially representative of sporadic AD. Indeed, it is notable that oxidative stress precedes Abeta deposition in Down syndrome (6) and neuronal oxidation has been observed to be accompanied by early diffuse deposition of Abeta1-42 (an AD-associated version of Abeta that is 42 residues in length) in a presymptomatic case with an autosomal-dominant AD mutation (7). In patients with very mild AD (clinical dementia rating = 0.5 on a functional measure of the severity of dementia scale with stages of 0, 0.5, 1, 2, and 3), we have found widespread intracellular oxidation in vulnerable neurons, whereas we have observed lower levels of oxidative damage in neurons that are adjacent to diffuse depositions of Abeta compared with the surrounding neurons (Fig. 1). When such an intraindividual observation of the inverse relationship between Abeta deposition and the level of neuronal oxidation is tested by interindividual analyses, it has been shown that an increasing amount of Abeta deposition is significantly associated with a decreasing level of neuronal oxidative damage in Down syndrome, sporadic AD, and familial AD (6-9). Of note, in our preliminary data, there may be an inverse relationship between the intraneuronal accumulation of Abeta1-42, mainly present as the monomeric form of the peptide, and oxidative damage (A. Nunomura, M. A. Smith, and G. Perry, unpublished observation), indicating that even the earliest alteration in the cellular Abeta metabolism may be associated with quenching oxidative stress.

Figure 1
View larger version (135K):
[in this window]
[in a new window]
Fig. 1. Lower level of oxidative damage in neurons adjacent to diffuse Abeta deposition. This image shows double immunolabeling of Abeta1-42 (brown) and 8-hydroxyguanosine (red), a marker for DNA/RNA oxidation, in the cerebral cortex of a subject with very mild AD (clinical dementia rating = 0.5). The section was counterstained with hematoxylin to identify nuclei (blue). The neurons (arrows) adjacent to diffuse Abeta deposition show a lower level of oxidative damage, as demonstrated by immunoreactivity for 8-hydroxyguanosine, as compared with surrounding neurons (arrowheads). Bar = 50 µm.

Abeta can be produced by numerous types of cells, such as neurons, astrocytes, neuroblastoma cells, hepatoma cells, fibroblasts, and platelets (10). This observation, together with its conserved sequence among different species, suggests that this peptide has an important function in normal cell development and maintenance. It might play a special role in neurons and smooth muscle cells, which show the highest levels of expression. Although an artificially high concentration of Abeta (in a micromolar range) can lead to oxidative stress in various biological systems (11), it is apparent from cell (12, 13), animal (14-18), and human (6) studies that oxidative stress chronologically precedes Abeta deposition.

Recently, in vitro and in vivo studies have demonstrated an antioxidant activity of Abeta. Monomeric Abeta1-40 (the most common form of Abeta) and Abeta1-42 have been shown to protect cultured neurons from iron- and copper-induced toxicity (19). In concord, coinjection of iron and Abeta1-42 into the rat cerebral cortex is significantly less toxic than injection of iron alone (20). Furthermore, the addition of physiological concentrations (in a low nanomolar range) of Abeta1-40 and Abeta1-42 has been shown to protect lipoproteins from oxidation in cerebrospinal fluid and plasma (21). These Abeta peptides fail to prevent metal-independent oxidation; moreover, Abeta25-35 [which lacks metal binding sites (histidine at positions 6, 13, and 14, and tyrosine at position 10)] is less effective than other versions of Abeta at inhibiting oxidation. Therefore, it is likely that the mechanism by which Abeta inhibits oxidation is via chelating metal ions (21). Indeed, copper, iron, and zinc concentrations are elevated in the rims and cores of Abeta plaques in postmortem brains of AD patients (22, 23). We suppose that chelation of redox-active copper and iron is the most important mechanism by which Abeta exerts its protective function and that elevation of zinc, a redox-inert antioxidant, may be a homeostatic response to oxidative stress, which subsequently accelerates the formation of Abeta plaques (24). Zinc binding has been shown to cause conformational changes in the Abeta peptide toward a more structured state. Zinc binding-induced Abeta aggregation might also result from the formation of intermolecular (histidine-zinc-histidine) bridges (25). The high affinity of Abeta for copper and zinc, its strong redox potential, and its ability to recruit O2 are features that resemble the electrochemistry of a genuine antioxidant, Cu,Zn superoxide dismutase (SOD1) (26).

By this logic, therefore, AD kindreds with APP mutations lose effective antioxidant capacity (as a result of mutation-driven protein dysfunction), whereas the extensive Abeta deposits themselves are signatures not of neurotoxicity per se but of oxidative imbalance and an oxidative-stress response. This idea is consistent with the findings that (i) the prevalence of biochemically detectable Abeta and immunocytochemically detectable Abeta deposits in cognitively normal aging individuals starts to increase around the age of 40 and 50, respectively (27, 28) (see Thal Perspective) and (ii) a large percentage of cognitively normal elderly contain Abeta loads equivalent to those of patients with AD (29). Conversely, Abeta is not always present in the brains of cognitively normal elderly. Whether this observation indicates that some individuals have efficient endogenous antioxidant defense systems, and thus age more effectively, or whether such individuals may have supplemented their diets with antioxidants throughout their life span, compensating for age-related declines in antioxidant defenses, remains to be elucidated (30, 31). If the process of Abeta deposition is closely associated with antioxidant function, this process will be recruited during times when oxidative stress is high and the endogenous antioxidant defenses are compromised. On the other hand, if this system is efficient and/or is supported by exogenous antioxidant supplementation, the anti-oxidant effects of Abeta may not be necessary.


In AD, neuronal loss and clinical severity correlate with NFT density; however, the number of neurons lost largely exceeds the number of neurons containing NFTs (32, 33). In a tau transgenic mouse in which the overexpression of mutant human tau can be regulated by tetracycline, turning off tau expression halts neuronal loss and reverses memory defects. But surprisingly, in this model, NFTs continue to accumulate, suggesting that NFTs are not responsible for neurodegeneration (34) (see SantaCruz Science article). This result is consistent with a report on transgenic mice expressing nonmutant human tau, in which neuronal death occurs independently of NFT formation (35). In a human study, an ultrastructural analysis demonstrated that a reduction in the number and total length of microtubules in pyramidal neurons (which integrate signals from different regions of the brain) in AD was unrelated to the presence of NFTs (36). Indeed, neurons with NFTs are estimated to be able to survive for decades (37), which suggests that NFTs themselves are not obligatory for neuronal death in AD.

Like Abeta, tau might also play an important role in antioxidant defenses. Cellular (38), animal (39), and human (6) studies suggest that oxidative stress chronologically precedes NFT formation. Oxidative stress activates several kinases, including glycogen synthase kinase-3 and mitogen-activated protein (MAP) kinases, which are activated in AD and are capable of phosphorylating tau. Once phosphorylated, tau becomes particularly vulnerable to oxidative modification and consequently aggregates into fibrils (40). Therefore, NFT formation is likely to be a result of neuronal oxidation. Furthermore, in neurons of postmortem AD brains, a decrease in oxidative damage in nucleic acids (mainly cytoplasmic RNAs) is associated with the presence of NFTs, as determined by a comparison of neurons with and without NFTs, an observation that is particularly striking in light of the abundance of RNA on NFTs (9).

Tau and neurofilament proteins that are modified by lipid peroxidation products and carbonyls (41-44) may work as a physiological "buffer" against toxic intermediates derived from oxidative reactions and thereby enhance neuronal survival. Although tau and neurofilaments are cytoskeletal proteins with long half lives, the extent of carbonyl modification is comparable in young and aged mice, as well as along the length of the axon (45). A logical explanation for this finding is that the oxidative modification of cytoskeletal proteins is under tight regulation. A high content of lysine-serine-proline (KSP) domains on both tau and neurofilament protein suggests that they are uniquely adapted to undergoing oxidative attack. Exposure of these domains on the protein surface is effected by extensive phosphorylation of the serine residues, resulting in an oxidative "sponge" of surface-accessible lysine residues, which are specifically modified by products of lipid peroxidation (45). Because phosphorylation plays this pivotal role in redox balance, it is not surprising that oxidative stress leads to phosphorylation through activation of MAP kinase pathways (46-48), nor that conditions associated with chronic oxidant stress, such as AD, are associated with extensive phosphorylation of cytoskeletal elements. Indeed, other neurological conditions in which phosphorylated tau and neurofilament protein accumulations occur (such as progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia) also show evidence of oxidative adducts on these proteins (49, 50). This protective role of tau phosphorylation explains the finding that embryonic neurons that survive after treatment with oxidants have more phospho-tau immunoreactivity relative to neurons under degeneration (51). Further, the induction of heme oxygenase, an antioxidant enzyme (which cleaves the oxidant heme) reduces tau expression and phosphorylation, indicating a crucial role for tau in redox homeostasis (43, 52). Supporting this notion, there is reduced oxidative damage in neurons with tau accumulation that we suspect is due to the antioxidant function of phosphorylated tau.


The concept that intracellular inclusions are manifestations of cell survival has recently found support in a Huntington's disease (HD) model (53). HD is caused by expansion of a polyglutamine tract in the huntingtin protein and is characterized by the formation of intraneuronal inclusions that contain mutant huntingtin (see Rubinsztein Perspective). In this neuronal model of HD, cell death was found to be dependent on both the dose of mutant huntingtin and the length of the polyglutamine tract; however, huntingtin inclusion formation correlated with cell survival. Thus, in this model, as in AD, inclusion formation represents adaptation, or a productive, beneficial response to the otherwise neurodegenerative process. Taken together with our studies, this result calls for a fundamental and necessary change in the way in which pathological manifestations of neurodegenerative disease are interpreted.

Amyloid-beta and Tau Oligomers

Although this Perspective highlights a protective function of the lesion-associated proteins against oxidative stress in AD, the efficiency of the protective function may be dependent on the aggregation state of the proteins (19). Recently, an increasing body of evidence has been collected to support the hypothesis that oligomers--rather than larger aggregates--represent the toxic fractions of Abeta and tau (54-57) (see Lashuel Perspective). More detective work is required before this small intermediate fraction (oligomers) can be convicted as the real culprit. However, if only the oligomeric fraction is detrimental and monomeric peptides per se as well as mature fibrils are protective, therapeutic approaches targeting the protein should be highly specific for the oligomeric aggregation state. Therefore, further study is required to adequately assess the relation between oxidative damage and oligomers of Abeta and tau, which may provide an important clue to early therapeutic intervention in AD.


The long-held notion that pathological lesions in neurodegenerative diseases provide direct insight into etiology may be a fundamental misconception. The observed decrease in oxidative damage with Abeta and tau accumulation suggests that senile plaques and NFTs are manifestations of cellular adaptation. Therapeutic strategy aimed solely at eliminating Abeta or tau may therefore be directed against a biochemical process that is more physiological than pathological and therefore unlikely to produce the desired results. We further suggest that the classical notion of the pathological hallmarks as signifying neurodegenerative disease should be reorganized into a modern framework that recognizes the difference between cause and effect. Only through such an effort will the greatest potential for continued diagnostic and therapeutic advances be realized.

May 3, 2006
  1. A. Alzheimer, Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschr. Psychiatr. 64, 146-148 (1907).
  2. B. T. Hyman, J. Q. Trojanowski, Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J. Neuropathol. Exp. Neurol. 56, 1095-1097 (1997).[CrossRef][Medline]
  3. S. S. Mirra, A. Heyman, D. McKeel, S. M. Sumi, B. J. Crain, L. M. Brownlee, F. S. Vogel, J. P. Hughes, G. van Belle, L. Berg, The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41, 479-486 (1991).[Abstract/Free Full Text]
  4. J. Hardy, D. J. Selkoe, The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 297, 353-356 (2002).[Abstract/Free Full Text]
  5. R. B. Knowles, T. Gómez-Isla, B. T. Hyman, Abeta associated neuropil changes: Correlation with neuronal loss and dementia. J. Neuropathol. Exp. Neurol. 57, 1122-1130 (1998).[Medline]
  6. A. Nunomura, G. Perry, M. A. Pappolla, R. P. Friedland, K. Hirai, S. Chiba, M. A. Smith, Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome, J. Neuropathol. Exp. Neurol. 59, 1011-1017 (2000).[Medline]
  7. A. Nunomura, S. Chiba, C.F. Lippa, P. Cras, R. N. Kalaria, A. Takeda, K. Honda, M. A. Smith, G. Perry, Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol. Dis. 17, 108-113 (2004).[CrossRef][Medline]
  8. A. Nunomura, G. Perry, M. A. Pappolla, R. Wade, K. Hirai, S. Chiba, M. A. Smith, RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J. Neurosci. 19, 1959-1964 (1999).[Abstract/Free Full Text]
  9. A. Nunomura, G. Perry, G. Aliev, K. Hirai, A. Takeda, E. K. Balraj, P. K. Jones, H. Ghanbari, T. Wataya, S. Shimohama, S. Chiba, C. S. Atwood, R. B. Petersen, M. A. Smith, Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759-767 (2001).[Medline]
  10. C. S. Atwood, M. E. Obrenovich, T. Liu, H. Chan, G. Perry, M. A. Smith, R. N. Martins, Amyloid-beta: A chameleon walking in two worlds: A review of the trophic and toxic properties of amyloid-beta. Brain Res. Brain Res. Rev. 43, 1-16 (2003).[CrossRef][Medline]
  11. A. Kontush, Amyloid-beta: An antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic. Biol. Med. 31, 1120-1131 (2001).[CrossRef][Medline]
  12. H. Misonou, M. Morishima-Kawashima, Y. Ihara, Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 39, 6951-6959 (2000).[CrossRef][Medline]
  13. D. Paola, C. Domenicotti, M. Nitti, A. Vitali, R. Borghi, D. Cottalasso, D. Zaccheo, P. Odetti, P. Strocchi, U. M. Marinari et al., Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem. Biophys. Res. Commun. 268, 642-646 (2000).[CrossRef][Medline]
  14. D. Praticò, K. Uryu, S. Leight, J. Q. Trojanowski, V. M. Lee, Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183-4187 (2001).[Abstract/Free Full Text]
  15. T. A. Bayer, S. Schafer, A. Simons, A. Kemmling, T. Kamer, R. Tepest, A. Eckert, K. Schussel, O. Eikenberg, C. Sturchler-Pierrat et al., Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 100, 14187-14192 (2003).[Abstract/Free Full Text]
  16. J. Drake, C. D. Link, D. A. Butterfield, Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol. Aging 24, 415-420 (2003).[CrossRef][Medline]
  17. F. Li, N. Y. Calingasan, F. Yu, W. M. Mauck, M. Toidze, C. G. Almeida, R. H. Takahashi, G. A. Carlson, M. Flint Beal, M. T. Lin, G. K. Gouras, Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J. Neurochem. 89, 1308-1312 (2004).[CrossRef][Medline]
  18. S. Sung, Y. Yao, K. Uryu, H. Yang, V. M. Lee, J. Q. Trojanowski, D. Praticò, Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer's disease. FASEB J. 18, 323-325 (2004).[Abstract/Free Full Text]
  19. K. Zou, J. S. Gong, K. Yanagisawa, M. Michikawa, A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J. Neurosci. 22, 4833-4841 (2002).[Abstract/Free Full Text]
  20. G. M. Bishop, S. R. Robinson, Human Abeta1-42 reduces iron-induced toxicity in rat cerebral cortex. J. Neurosci. Res. 73, 316-323 (2003).[CrossRef][Medline]
  21. A. Kontush, C. Berndt, W. Weber, V. Akopyan, S. Arlt, S. Schippling, U. Beisiegel, Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med. 30, 119-128 (2001).[CrossRef][Medline]
  22. M. A. Lovell, J. D. Robertson, W. J. Teesdale, J. L. Campbell, W. R. Markesbery, Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158, 47-52 (1998).[CrossRef][Medline]
  23. J. Dong, C. S. Atwood, V. E. Anderson, S. L. Siedlak, M. A. Smith, G. Perry, P. R. Carey, Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 42, 2768-2773 (2003).[CrossRef][Medline]
  24. M. P. Cuajungco, L. E. Goldstein, A. Nunomura, M. A. Smith, J. T. Lim, C. S. Atwood, X. Huang, Y. W. Farrag, G. Perry, A. I. Bush, Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of Abeta by zinc. J. Biol. Chem. 275, 19439-19442 (2000).[Abstract/Free Full Text]
  25. S. Zirah, S. A. Kozin, A. K. Mazur, A. Blond, M. Cheminant, I. Segalas-Milazzo, P. Debey, S. Rebuffat, Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging. J. Biol. Chem. 281, 2151-2161 (2006).[Abstract/Free Full Text]
  26. C. C. Curtain, F. Ali, I. Volitakis, R. A. Cherny, R. S. Norton, K. Beyreuther, C. J. Barrow, C. L. Masters, A. I. Bush, K. J. Barnham, Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 276, 20466-20473 (2001).[Abstract/Free Full Text]
  27. L. Davies, B. Wolska, C. Hilbich, G. Multhaup, R. Martins, G. Simms, K. Beyreuther, C. L. Masters, A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38, 1688-1693 (1988).[Abstract/Free Full Text]
  28. H. Funato, M. Yoshimura, K. Kusui, A. Tamaoka, K. Ishikawa, N. Ohkoshi, K. Namekata, R. Okeda, Y. Ihara, Quantitation of amyloid beta -protein (Abeta) in the cortex during aging and in Alzheimer's disease. Am. J. Pathol. 152,1633-1640 (1998).[CrossRef][Medline]
  29. D. G. Davis, F. A. Schmitt, D. R. Wekstein, W. R. Markesbery, Alzheimer neuropathologic alterations in aged cognitively normal subjects. J. Neuropathol. Exp. Neurol. 58, 376-388 (1999).[CrossRef][Medline]
  30. J. A. Joseph, B. Shukitt-Hale, N. A. Denisova, R. L. Prior, G. Cao, A. Martin, G. Taglialatela, P. C. Bickford, Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J. Neurosci. 18, 8047-8055 (1998).[Abstract/Free Full Text]
  31. J. A. Joseph, B. Shukitt-Hale, N. A. Denisova, D. Bielinski, A. Martin, J. J. McEwen, P. C. Bickford, Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci. 19, 8114-8121 (1999).[Abstract/Free Full Text]
  32. T. G�mez-Isla, R. Hollister, H. West, S. Mui, J. H. Growdon, R. C. Petersen, J. E. Parisi, B. T. Hyman, Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17-24 (1997).[CrossRef][Medline]
  33. J. J. Kril, S. Patel, A. J. Harding, G. M. Halliday, Neuron loss from the hippocampus of Alzheimer's disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol. (Berl.) 103, 370-376 (2002).[CrossRef][Medline]
  34. K. SantaCruz, J. Lewis, T. Spires, J. Paulson, L. Kotilinek, M. Ingelsson, A. Guimaraes, M. DeTure, M. Ramsden, E. McGowan et al., Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476-481 (2005).[Abstract/Free Full Text]
  35. C. Andorfer, C. M. Acker, Y. Kress, P. R. Hof, K. Duff, P. Davies, Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. 25, 5446-5454 (2005).[Abstract/Free Full Text]
  36. A. D. Cash, G. Aliev, S. L. Siedlak, A. Nunomura, H. Fujioka, X. Zhu, A. K. Raina, H. V. Vinters, M. Tabaton, A. B. Johnson, M. Paula-Barbosa, J. Avila, P. K. Jones, R. J. Castellani, M. A. Smith, G. Perry, Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am. J. Pathol. 162, 1623-1627 (2003).[CrossRef][Medline]
  37. R. Morsch, W. Simon, P. D. Coleman, Neurons may live for decades with neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 188-197 (1999).[CrossRef][Medline]
  38. A. Gomez-Ramos, J. Diaz-Nido, M. A. Smith, G. Perry, J. Avila, Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J. Neurosci. Res. 71, 863-870 (2003).[CrossRef][Medline]
  39. H. Nakashima, T. Ishihara, O. Yokota, S. Terada, J. Q. Trojanowski, V. M. Lee, S. Kuroda, Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic. Biol. Med. 37, 176-186 (2004).[CrossRef][Medline]
  40. H. G. Lee, G. Perry, P. I. Moreira, M. R. Garrett, Q. Liu, X. Zhu, A. Takeda, A. Nunomura, M. A. Smith, Tau phosphorylation in Alzheimer's disease: Pathogen or protector? Trends Mol. Med. 11, 164-169 (2005).[CrossRef][Medline]
  41. M. A. Smith, M. Rudnicka-Nawrot, P. L. Richey, D. Praprotnik, P. Mulvihill, C. A. Miller, L. M. Sayre, G. Perry, Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J. Neurochem. 64, 2660-2666 (1995).[Medline]
  42. L. M. Sayre, D. A. Zelasko, P. L. Harris, G. Perry, R. G. Salomon, M. A. Smith, 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J. Neurochem. 68, 2092-2097 (1997).[Medline]
  43. A. Takeda, M. A. Smith, J. Avila, A. Nunomura, S. L. Siedlak, X. Zhu, G. Perry, L. M. Sayre, In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J. Neurochem. 75, 1234-1241 (2000).[CrossRef][Medline]
  44. N. Y. Calingasan, K. Uchida, G. E. Gibson, Protein-bound acrolein: A novel marker of oxidative stress in Alzheimer's disease. J. Neurochem. 72, 751-756 (1999).[CrossRef][Medline]
  45. T. Wataya, A. Nunomura, M. A. Smith, S. L. Siedlak, P. L. Harris, S. Shimohama, L. I. Szweda, M. A. Kaminski, J. Avila, D. L. Price et al., High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J. Biol. Chem. 277, 4644-4648 (2002).[Abstract/Free Full Text]
  46. X. Zhu, C. A. Rottkamp, H. Boux, A. Takeda, G. Perry, M. A. Smith, Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J. Neuropathol. Exp. Neurol. 59, 880-888 (2000).[Medline]
  47. X. Zhu, R. J. Castellani, A. Takeda, A. Nunomura, C. S. Atwood, G. Perry, M. A. Smith, Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: The "two hit" hypothesis. Mech. Ageing Dev. 123, 39-46 (2001).[CrossRef][Medline]
  48. X. Zhu, A. K. Raina, C. A. Rottkamp, G. Aliev, G. Perry, H. Boux, M. A. Smith, Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J. Neurochem. 76, 435-441 (2001).[CrossRef][Medline]
  49. P. Odetti, S. Garibaldi, R. Norese, G. Angelini, L. Marinelli, S. Valentini, S. Menini, N. Traverso, D. Zaccheo, S. Siedlak et al., Lipoperoxidation is selectively involved in progressive supranuclear palsy. J. Neuropathol. Exp. Neurol. 59, 393-397 (2000).[Medline]
  50. R. Castellani, M. A. Smith, P. L. Richey, R. Kalaria, P. Gambetti, G. Perry, Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res. 696, 268-271 (1995).[CrossRef][Medline]
  51. F. J. Ekinci, T. B. Shea, beta-amyloid-induced tau phosphorylation does not correlate with degeneration in cultured neurons. J. Alzheimers Dis. 2, 7-15 (2000).[Medline]
  52. A. Takeda, G. Perry, N. G. Abraham, B. E. Dwyer, R. K. Kutty, J. T. Laitinen, R. B. Petersen, M. A. Smith, Overexpression of heme oxygenase in neuronal cells, the possible interaction with Tau. J. Biol. Chem. 275, 5395-5399 (2000).[Abstract/Free Full Text]
  53. M. Arrasate, S. Mitra, E. S. Schweitzer, M. R. Segal, S. Finkbeiner, Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805-810 (2004).[CrossRef][Medline]
  54. C. A. McLean, R. A. Cherny, F. W. Fraser, S. J. Fuller, M. J. Smith, K. Beyreuther, A. I. Bush, C. L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860-866 (1999).[CrossRef][Medline]
  55. D. M. Walsh, I. Klyubin, J. V. Fadeeva, W. K. Cullen, R. Anwyl, M. S. Wolfe, M. J. Rowan, D. J. Selkoe, Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539 (2002).[CrossRef][Medline]
  56. S. Sato, Y. Tatebayashi, T. Akagi, D. H. Chui, M. Murayama, T. Miyasaka, E. Planel, K. Tanemura, X. Sun, T. Hashikawa et al., Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells. J. Biol. Chem. 277, 42060-42065 (2002).[Abstract/Free Full Text]
  57. S. Maeda, N. Sahara, Y. Saito, S. Murayama, A. Ikai, A. Takashima, Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer's disease. Neurosci. Res. 54, 197-201 (2006).[CrossRef][Medline]
Citation: A. Nunomura, R. J. Castellani, H. Lee, P. I. Moreira, X. Zhu, G. Perry, M. A. Smith, Neuropathology in Alzheimer's Disease: Awaking from a Hundred-Year-Old Dream. Sci. Aging Knowl. Environ. 2006 (8), pe10 (2006).

Science of Aging Knowledge Environment. ISSN 1539-6150