title: Intrahippocampal administration of amyloid-β(1-42) oligomers acutely impairs spatial working memory, insulin signaling, and hippocampal metabolism.
abstract: Increasing evidence suggests that abnormal brain accumulation of amyloid-β(1-42) (Aβ(1-42)) 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, Aβ(1-42) 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 Aβ(1-42) oligomers could acutely impair hippocampal metabolic and cognitive processes in vivo in the rat. Our findings support this hypothesis: Aβ(1-42) oligomers impaired spontaneous alternation behavior while preventing the task-associated dip in hippocampal ECF glucose observed in control animals. In addition, Aβ(1-42) 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 Aβ(1-42) oligomers can rapidly impair hippocampal cognitive and metabolic processes, and provide support for the hypothesis that elevated Aβ(1-42) leads to cognitive impairment via interference with hippocampal insulin signaling.
authors.affiliation: Behavioral Neuroscience, University at Albany, Albany, NY, USA. jp973156@albany.edu
authors.forename: Jiah
authors.initials: J
authors.lastname: Pearson-Leary
authors.forename: Ewan C
authors.initials: EC
authors.lastname: McNay
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; C495694:Slc2a4 protein, rat; C075222:amyloid beta-protein (1-42); D005947:Glucose