GPER in murine astrocytes and mural cells promotes neurovascular coupling and Aβ clearance

Alzheimer's disease (AD) affects aged women more than men. The precipitous drop in sex hormone levels in postmenopausal women likely contributes to such sexual dimorphism, with emerging evidence implicating the G protein-coupled estrogen receptor (GPER) as a modulator of AD pathology and cognitive impairments. However, the underlying mechanism remains unknown. GPER is distinctively expressed in key components of the neurovascular unit (NVU), namely astrocytes and mural cells (specifically, pericytes). Using GPER-knockout (GPER-KO) and APP/PS1 transgenic AD mouse models, here we show that GPER deficiency exacerbates Aβ deposition, impairs spatial and working memory, and disrupts neurovascular coupling. GPER activation in pericytes reinforces Lrp1-dependent endocytic uptake of Aβ. In astrocytes, GPER appears to be essential in regulation of AQP4 polarity, gap junction protein expression and reactivity. Furthermore, GPER interacts directly with Aβ to form a protein complex and loss of GPER leads to astrocytic dysfunction, reduced pericyte coverage, and impaired glymphatic clearance. Our findings reveal GPER as a critical regulator of NVU function and Aβ proteostasis, providing a mechanistic basis for AD sexual dimorphism, further supporting GPER as a potential target for sex-specific therapeutic strategies.