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}case.edu (M.A.S.), nuno{at}asahikawa-med.ac.jp (A.N.)

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

Abstract: For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid- (A) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with A and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That A and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.

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).