Role of Abca7-related microglial responses in linking type 2 diabetes mellitus to Alzheimer's Disease progression: Evidence from single-cell transcriptomic analysis and experimental validation in animal and cell models.

Abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share overlapping pathological mechanisms characterized by neuroinflammation and metabolic dysfunction, yet the underlying mechanisms remain elusive. In this study, we aimed to investigate the potential involvement of Abca7 in the microglial responses linking AD and T2DM. Single-cell RNA sequencing (scRNA-seq) data from the hippocampi of db/db and db/m mice were analyzed to characterize cellular heterogeneity. To validate the bioinformatic findings, an AD mouse model was established by a single intracerebroventricular injection of Aβ1-42. Behavioral performances were observed, and the protein expression of Abca7 and typical neuropathological features of AD were detected. In parallel, in vitro studies were conducted using BV2 microglial cells exposed to Aβ1-42 following Abca7 knockdown. The scRNA-seq analysis revealed significant alterations in endothelial cells, microglia, and oligodendrocytes in db/db mice. Microglia emerged as central regulators of neuroinflammatory responses, with Abca7 identified as a hub gene linked to both T2DM and AD pathology. Consistently, the expression of Abca7 in the hippocampus of AD mice was markedly elevated and positively correlated with the cognitive impairments and Aβ/Tau pathology. Moreover, the knockdown of Abca7 could protect BV2 cells against Aβ-induced injuries and hyperactivation which could be partly ascribed to the suppression of NF-κB signaling and oxidative stress. Overall, these results suggest Abca7 may play a linking role in the microglial response between T2DM and AD, which is partly supported by in vivo and in vitro results of its effect on the hyperactivation of microglia in AD-like pathologies.