Amyloid-derived diffusible ligands acutely impair spatial memory and hippocampal insulin signaling

Abstract

The exact mechanism underlying cognitive deficits associated with AD remains unknown; however, both elevated levels of amyloid-derived diffusible ligands (ADDLs) and impaired brain insulin signalling are associated with AD, and ADDLs have been shown in vitro to impair hippocampal insulin signalling. We recently demonstrated that intact hippocampal insulin signalling is required for optimal cognitive functioning; hence, we hypothesized that ADDLs may directly impair memory by attenuating hippocampal insulin signalling. Rats were given either ADDLS or vehicle to the left hippocampus 10 min prior to testing in a four-arm maze using a spatial memory (spontaneous alternation) task. In vivo microdialysis was used to examine the impact of ADDL adminstration on local hippocampal metabolism, and post mortem analyses of insulin signalling were performed. ADDL administration significantly impaired memory performance, GluT translocation, and insulin signalling. ADDLs act rapidly to downregulate hippocampal insulin signalling, leading directly to impaired cognitive performance. These data demonstrate, in vivo, acute amyloid-induced cognitive impairment and support the hypothesis that such impairment is via downregulation of hippocampal insulin signalling.