Additions to Alpha-Sheet Based Hypotheses for the Cause of Alzheimer's Disease

Philip Serwer, Elena T. Wright, Barbara Hunter

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer's disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α-sheet-like backbone (α-structured) subsequently detoxified by intracellular α-to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200-2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α-structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α-structure-based hypotheses: 1) Lipofuscin-associated, α-structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α-to-β detoxification of α-structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD.

Original languageEnglish (US)
Pages (from-to)429-438
Number of pages10
JournalJournal of Alzheimer's Disease
Issue number2
StatePublished - 2022


  • Alpha-sheet
  • amyloid
  • electron microscopy
  • lipofuscin
  • molecular model
  • thin sectioning

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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