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

摘要

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-beta peptide (A beta(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 A beta(1-42) monomers could improve the impaired memory not only in cDKO mice without A beta(1-42) deposition but also in the APP/PS1/Tau triple transgenic 3 x Tg-AD mice with A beta(1-42) deposition, which were mediated by alpha 7-nAChR. Our findings demonstrate for the first time that reduced soluble A beta(1-42) level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble A beta(1-42) level due to A beta(1-42) deposition may also cause cognitive deficits in 3 x Tg-AD mice. Therefore, "loss-of-function" of A beta(1-42) should be avoided when designing therapies aimed at reducing A beta(1-42) burden in AD.

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