Affiliations: Behavioral Neuroscience, University at Albany, Albany, NY, USA
Correspondence:
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Correspondence to: Jiah Pearson-Leary, University at Albany, 1400 Washington Ave, 1003H LSRB, Albany, NY 12222, USA. Tel.: +1 518 437 4452; E-mail: jp973156@albany.edu.
Abstract: Increasing evidence suggests that abnormal brain accumulation of amyloid-β1-42 (Aβ1-42) oligomers plays a causal role in Alzheimer's disease (AD), and in particular may cause the cognitive deficits that are the hallmark of AD. In vitro, Aβ1-42 oligomers impair insulin signaling and suppress neural functioning. We previously showed that endogenous insulin signaling is an obligatory component of normal hippocampal function, and that disrupting this signaling led to a rapid impairment of spatial working memory, while delivery of exogenous insulin to the hippocampus enhanced both memory and metabolism; diet-induced insulin resistance both impaired spatial memory and prevented insulin from increasing metabolism or cognitive function. Hence, we tested the hypothesis that Aβ1-42 oligomers could acutely impair hippocampal metabolic and cognitive processes in vivo in the rat. Our findings support this hypothesis: Aβ1-42 oligomers impaired spontaneous alternation behavior while preventing the task-associated dip in hippocampal ECF glucose observed in control animals. In addition, Aβ1-42 oligomers decreased plasma membrane translocation of the insulin-sensitive glucose transporter 4 (GluT4), and impaired insulin signaling as measured by phosphorylation of Akt. These data show in vivo that Aβ1-42 oligomers can rapidly impair hippocampal cognitive and metabolic processes, and provide support for the hypothesis that elevated Aβ1-42 leads to cognitive impairment via interference with hippocampal insulin signaling.
Keywords: Amyloid, glucose, glucose transporter type 4, hippocampal, insulin, memory
