LAUSR

ABSTRACT Amyloid &bgr; (A&bgr;) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of A&bgr; is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD‐associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus‐dependent memory impairments using A&bgr;‐injected as well as 5XFAD AD model mice. Oligomeric A&bgr; injections into the 3rd ventricle caused concentration‐dependent and time‐dependent impairments in learning/memory and synaptic plasticity. Moreover, A&bgr; aberrantly regulated caspase‐3, GSK‐3&bgr;, and Akt signaling, which interact with each other in the hippocampus. Caspase‐3 and GSK‐3&bgr; inhibitor ameliorated memory impairments and synaptic deficits in A&bgr;‐injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both A&bgr;‐treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD. HIGHLIGHTSOligomeric A&bgr; impaired learning and memory and synaptic plasticity.Caspase inhibition ameliorated A&bgr;‐induced deficits.Akt activation ameliorated A&bgr;‐induced deficits.GSK‐3&bgr; inhibition ameliorated A&bgr;‐induced deficits.Akt activation ameliorated learning and memory and synaptic deficits in 5XFAD mice.