Exogenous Aβ1-42 monomers improve synaptic and cognitive function in Alzheimer's disease model mice

Abstract

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ_1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ_1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ_1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ_1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ_1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ_1-42 level due to Aβ_1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, "loss-of-function" of Aβ_1-42 should be avoided when designing therapies aimed at reducing Aβ_1-42 burden in AD.

Keywords: AD; Aβ(1-42); Memory; Presenilins; a7-nAchR.