Abstract Body

Cholinergic deficiency is a hallmark of many neurodegenerative disorders including Alzheimer’s disease (AD). Decreased levels of the vesicular acetylcholine transporter (VAChT) have been detected in AD and imaging data suggest that VAChT levels can predict human pathology. Decreased forebrain VAChT levels cause cognitive dysfunction, however, whether changes in VAChT levels are causally associated with plaque formation is unknown. We tested this by generating humanized APP knock-in (KI) mice lacking VAChT in cholinergic forebrain neurons and humanized APP knock-in (KI) mice overexpressing VAChT. In males, elimination of forebrain VAChT led to increased plaque area and Ab levels compared to AD mice expressing normal levels of VAChT. In contrast, male mice with VAChT overexpression showed decreased Ab levels. Surprisingly, this causal relationship was not found in intact female mice. In contrast, in female mice submitted to ovariectomy, to reduce a major source of sex hormones, the causal relationship between VAChT levels and amyloid pathology was restored. Interestingly, a similar sexual dimorphism was observed when analyzing glial cells association to plaques, suggesting the possibility that sexual dimorphic glial responses are modulated by cholinergic signaling. In humans, VAChT levels have been associated to AD pathology in both males and females. Our experiments suggest that cholinergic regulation of plaque pathology is not observed in intact female mice, pointing to an important effect of sexual hormones for cholinergic regulation of plaque pathology. These results suggest that VAChT has a causal relationship with AD pathology and that ovariectomized mice may better mimic AD pathological changes in post-menopausal women.