期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 68, 期 2, 页码 493-510出版社
IOS PRESS
DOI: 10.3233/JAD-180802
关键词
Alpha-secretase; Alzheimer's disease; amyloid hypothesis; amyloid plaque; amyloid-alpha peptide; amyloid-beta peptide; amyloid precursor protein; apolipoprotein E; beta-secretase; inherited Alzheimer's disease; non-inherited Alzheimer's disease
资金
- Ministero della Salute, I.R.C.C.S. Research Program, Ricerca Corrente 2018-2020, Linea n. 2 Meccanismi genetici, predizione e terapie innovative delle malattie complesse
- 5x1000 voluntary contribution
The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-beta (A beta) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model A beta peptides act as neurotoxic molecules, but only above a critical concentration [A beta](c). A threshold mechanism triggers IAD/NIAD onset only when [A beta]>=[A beta](c). In this process, APOE modifies [A beta](c) threshold in an isoform-specific way. Consequently, all factors influencing A beta anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or A beta catabolism/clearance could contribute to exceed the threshold [A beta](c), being characteristic of each individual. In this model, AP formation does not depend on [A beta](c). The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
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