More On Depletion of Soluble Amyloid- β in Alzheimer ' s Disease

If slow amyloid-β aggregation over years is the cause of Alzheimer's disease, then how to explain the older individuals who have high levels of amyloid-β in the brain, but do not suffer from Alzheimer's disease? Further, how to explain the failure of amyloid-β clearance via immunotherapy in clinical trials? Amyloid-β is successfully cleared from the brain, but patient outcomes do not improve meaningfully. This line of thinking led to the hypothesis, with supporting evidence, that amyloid-β aggregation is pathological only because it depletes levels of soluble amyloid-β. It doesn't cause that issue to the same degree in every older individual, however, and individuals who manage to maintain high levels of soluble amyloid-β avoid Alzheimer's disease even when they have a large burden of amyloid-β aggregates. Key support for the toxic amyloid hypothesis comes from the observation that mutations in any of three genes (APP, PSEN1, and PSEN2) lead to Alzheimer's disease (AD). The genetic evidence causally implicates the fibrillogenic 42-amino acid amyloid-β peptide (Aβ42). However, the disease pathogenesis may arise from either of two ends of the protein aggregation process: the increase in insoluble amyloid plaques or the depletion of the soluble Aβ42 peptide, which has important functions. While insoluble amyloid plaques can be present in normal individuals, low soluble levels of Aβ42 are an invariable feature of AD. The hypothesis of Aβ toxicity has ...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs