The lysosomal-associated membrane protein 2-macroautophagy pathway is involved in the regulatory effects of hippocampal aromatase on Aβ accumulation and AD-like behavior

Abstract

Aims

Hippocampal aromatase (AROM) knockdown induces Aβ accumulation and Alzheimer's disease (AD)-like spatial learning and memory impairment, and early hippocampal AROM overexpression in APP/PS1 mice prevents Aβ deposition and memory loss later in life. The aim of this study was to elucidate the underlying mechanism and provide novel prevention and treatment targets for AD.

Materials and methods

AROM-inhibiting viral vectors were constructed and injected into the hippocampi of adult female mice, after which label-free LC–MS/MS proteomics and bioinformatics analysis were conducted. Additional viral vectors targeting LAMP2 or LC3 were constructed and used to treat HT22 cells. LAMP2 expression was verified, and macroautophagy levels, autophagosome formation and Aβ accumulation were examined. Additionally, ovariectomy combined with the hippocampal injection of LAMP2 inhibition/overexpression viral vectors was applied, and learning and memory abilities and Aβ accumulation were examined.

Key findings

Proteomics revealed the enrichment of CMA and autophagy, and LAMP2 was the most significantly upregulated protein. Higher LAMP2 levels were correlated with lower macroautophagy and autophagosomes levels but were correlated with higher Aβ accumulation, and vice versa. Additionally, hippocampal LAMP2 mediated the effects of ovariectomy on spatial memory and Aβ accumulation.

Significance

These results demonstrated the important role of the hippocampal LAMP2-macroautophagy pathway in mediating both hippocampal and ovarian estrogen regulation of Aβ accumulation and AD-like behavior, indicating that LAMP2 might be a novel target for both hippocampal and circulating estrogen deficiency-associated memory impairments, such as AD.