Sex‐dependent cholinergic effects on amyloid pathology: A translational study

Abstract

INTRODUCTIONAbout two‐thirds of Alzheimer's Disease (AD) patients are women, who exhibit more severe pathology and cognitive decline than men. Whether biological sex causally modulates the relationship between cholinergic signaling and amyloid pathology remains unknown.METHODSWe quantified amyloid beta (Aβ) in male and female App‐mutant mice with either decreased or increased cholinergic tone and examined the impact of ovariectomy and estradiol replacement in this relationship. We also investigated longitudinal changes in basal forebrain (cholinergic function) and Aβ in elderly individuals.RESULTSWe show a causal relationship between cholinergic tone and amyloid pathology in males and ovariectomized female mice, which is decoupled in ovary‐intact and ovariectomized females receiving estradiol. In elderly humans, cholinergic loss exacerbates Aβ.DISCUSSIONOur findings emphasize the importance of reflecting human menopause in mouse models. They also support a role for therapies targeting estradiol and cholinergic signaling to reduce Aβ.Highlights Cholinergic tone regulates amyloid beta (Aβ) pathology in males and ovariectomized female mice. Estradiol uncouples the relationship between cholinergic tone and Aβ. In elderly humans, cholinergic loss correlates with increased Aβ in both sexes.

Effect of hormone replacement therapy on amyloid beta (Aβ) plaque density in the rhesus macaque amygdala

“…Taken together, the present results demonstrate that estradiol HRT can significantly reduce Aβ plaque load in the amygdala of surgically menopausal females, even when consuming a WSD. Because of concern about adverse peripheral side effects associated with conventional HRT, it is unclear if a hormonal-based therapies would gain acceptance by post-menopausal women ( German-Castelan et al, 2023 ). One possible way to overcome this potential problem, however, could be to rely on brain-selective prodrugs, such as 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) ( Tschiffely et al, 2016 ), as alternatives to traditionally used estrogens.…”

p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

“…T 1 -weighted three-dimensional sMRI scans were obtained before and at the end of treatment (Extended Data Table 2). Longitudinal changes in gray matter volumes were computed in MATLAB, as described previously 91 . Major steps in the sMRI pipeline were longitudinal registration of scans using the serial longitudinal pipeline 92 in Statistical Parametric Mapping Software version 7771 (https://www.fil.ion.ucl.ac.uk/ spm/software/spm12/), segmentation of brain tissue classes in the Computational Anatomy Toolbox (CAT12; version 12.8.1) 93 and spatial normalization to a population template that was created using the clinical trial sMRI data 94 .…”

Pathological Markers of Alzheimer’s Disease and Related Dementia in the Rhesus Macaque Amygdala

“…Like humans, rhesus macaques show an age-related increase in Aβ plaque density [ 12–16 ], which becomes especially evident within their amygdala after ∼20 years of age [ 17 ]. Furthermore, this Aβ plaque density has been shown to be significantly lower in old surgically menopausal (i.e., ovariectomized) females if they receive estradiol hormone replacement therapy (ERT) [ 17 ]; a finding that is consistent with the idea that hormone replacement may help to reduce Aβ in postmenopausal women [ 18 ]. In contrast, few rhesus macaque studies have focused on pTau [ 19, 20 ] or TDP-43 [ 21 ], and although these proteins have been detected during old age, they do not appear to be clearly linked to neuronal pathology or dementia.…”