Acromegalic Rat Model Presented Cognitive Impairments and Tau Hyperphosphorylation in the Hippocampus

Abstract

Introduction: Acromegaly patients, in addition to the most prominent physical and endocrine changes, also exhibit a higher risk of cognitive dysfunction. However, the reasons and mechanisms underlying cognitive impairments in acromegaly patients remain unknown. Methods: Acromegalic rats were induced by subcutaneous injection of tumor cells, with continuous monitoring of the body weight and hormones to confirm the occurrence of acromegaly. Behavioral assessments, including open field test, novel object recognition test, and Barnes maze test, were conducted to evaluate the animals’ cognitive function. Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to examine changes in the hippocampal tau protein, Aβ, and associated signaling pathways. Results: The tumor cells secreting growth hormone increased the secretion of growth hormone, resulting in changes in body size and endocrine functions, thus causing acromegaly. The acromegaly model showed deficiencies in working memory and spatial memory. Hyperphosphorylation of tau protein was observed in the hippocampus of the acromegaly model, but no Aβ deposition was observed. The acromegaly model exhibits hippocampal growth hormone (GH) resistance, decreased expression of GH receptors, and subsequently reduced expression activity of the PI3K-Akt-GSK3β signaling pathway, which is responsible for the hyperphosphorylation of tau protein. Conclusion: The prolonged elevation of GH and insulin-like growth factor 1 caused by acromegaly may lead to abnormalities in the SD rat’s PI3K-Akt-GSK3β signaling pathway, subsequently resulting in hyperphosphorylation of the hippocampal tau protein and cognitive impairment.