Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model

TLDR

Alzheimer’s disease therapies largely target amyloid‑β, yet the role of tau in mediating Aβ‑induced cognitive deficits remains uncertain. Lowering endogenous tau in APP transgenic mice prevented behavioral impairments and protected against excitotoxicity, indicating that tau reduction can block Aβ‑ and excitotoxin‑induced neuronal dysfunction and may be a viable therapeutic approach.

Abstract

Many potential treatments for Alzheimer's disease target amyloid-β peptides (Aβ), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Aβ-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Aβ levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Aβ- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.