Effect of intrahippocampal injection of amyloid-β1–42 on insulin levels and dendritic morphology in hippocampal neurons of male Wistar rats with metabolic syndrome

This study aimed to evaluate the effect of Aβ1–42 on the hippocampus of male Wistar rats under MS conditions, by studying alterations in brain insulin homeostasis and dendritic morphology. Male Wistar rats were fed either a standard diet (SD) or a high-carbohydrate diet (HCD) for six months to induce the MS phenotype. Animals with SD were designated the control group (Ctrl). Subsequently, animals in the MS and Ctrl groups were injected bilaterally intrahippocampally with either the Aβ1–42 peptide or isotonic saline solution (ISS), resulting in four experimental groups: Ctrl+ISS; Ctrl+Aβ1–42; MS + ISS; and MS + Aβ1–42. Thirty days after hippocampal injection, recognition memory was assessed using the Novel Object Recognition Test (NORt). Subsequently, the concentrations of insulin, Aβ1–42, and insulin-degrading enzyme (IDE) were quantified in the hippocampus. Dendritic morphology was also analyzed in the CA1, CA3, and dentate gyrus (DG) subregions of the hippocampus using Golgi-Cox staining. The 24 animals fed the HCD (100%) met the predefined operational criteria for the MS phenotype and were therefore eligible for hippocampal injection with Aβ1–42. When assessing recognition memory, the MS + Aβ1–42 group showed greater memory deficits compared to the other experimental groups. Insulin and Aβ1–42 levels in the hippocampus were higher in the MS + Aβ1–42 animals. However, the IDE was lower compared to the other groups. Morphological analyses demonstrated more severe reductions in dendritic branching, total dendritic length, and dendritic spine density in CA1, CA3, and DG neurons in the MS + Aβ1–42 group. Our results suggest that Aβ1–42-induced neurotoxicity in the hippocampus exacerbates the deterioration of dendritic morphology in hippocampal neurons, leading to greater memory deficits in male animals with the MS phenotype. A mechanistic link may exist between Aβ1–42 toxicity and central and peripheral metabolic dysfunction, highlighting insulin and IDE as potential therapeutic approaches to delay hippocampal neurodegeneration.