Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity

Amyloid beta (A beta) 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 beta 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 beta-injected as well as 5XFAD AD model mice. Oligomeric A beta injections into the 3rd ventricle caused concentration-dependent and time dependent impairments in learning/memory and synaptic plasticity. Moreover, A beta aberrantly regulated caspase-3, GSK-3 beta, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3 beta inhibitor ameliorated memory impairments and synaptic deficits in A beta-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both A beta-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD. (C) 2017 Elsevier Ltd. All rights reserved.