Amyloid-β and τ in alzheimerߣs disease: What is the neuropathology trying to tell us?

Rudy J. Castellani, Akihiko Nunomura, Hyoung Gon Lee, Xiongwei Zhu, George Perry, Mark A. Smith

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

For nearly a century, the pathological hallmarks of Alzheimer’s disease (AD), namely, senile plaques and neurofibrillary tangles (NFT), have provided a reasonable basis to conclude that their major components, amyloid-β and tau, respectively, are central mediators of disease pathogenesis. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the biochemistry of amyloid- β deposition as senile plaques, or the phosphorylation and aggregation of tau as NFT. Unfortunately, it now appears that this focus on pathology as a central contributor to disease may be misguided. In fact, rather than being initiators of disease pathogenesis, recent evidence shows that the lesions not only occur consequent to oxidative stress but, importantly, that they may function as a primary line of antioxidant defense. In this paradigm, it is not surprising that the increased sensitivity to oxidative stress in the aged brain, even in control individuals, is marked by the appearance of both amyloid-β and tau. Moreover in AD, where chronic oxidative stress persists and is superimposed upon an age-related vulnerable environment, an increased lesion load is predictable. That amyloid-β and tau accumulations serve as age-related physiological reactions 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 structure a paradigm shift before significant progress can be made in terms of therapeutic intervention.

Original languageEnglish (US)
Title of host publicationOxidative Stress and Age-Related Neurodegeneration
PublisherCRC Press
Pages121-130
Number of pages10
ISBN (Electronic)9781420026559
ISBN (Print)9780849337253
StatePublished - Jan 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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