Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

TLDR

Alzheimer disease is characterized by amyloid‑β plaques and hyperphosphorylated tau tangles, yet the temporal link between these lesions and the role of soluble oligomers remains unclear. The study aims to determine whether soluble Aβ dimers alone can initiate tau phosphorylation and neuritic degeneration. Researchers isolated the most abundant soluble Aβ dimers from AD cortex and showed that subnanomolar concentrations induce tau phosphorylation at disease‑relevant sites, disrupt microtubules, and cause neuritic degeneration without amyloid fibrils. Natural Aβ dimers isolated from AD cortex potently trigger tau hyperphosphorylation and neuritic degeneration at subnanomolar levels, whereas synthetic dimers are less effective; tau knockdown blocks, overexpression enhances, and N‑terminal antibodies or passive immunotherapy neutralize these effects.

Abstract

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.