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

Area of Science:

• Neuroscience
• Endocrinology
• Gerontology

Background:

• Alzheimer's Disease (AD) disproportionately affects women, with greater pathology and cognitive decline.
• The influence of biological sex on the interplay between cholinergic signaling and amyloid pathology in AD is not fully understood.

Purpose of the Study:

• To investigate the causal relationship between cholinergic tone and amyloid pathology in male and female mice.
• To examine the role of ovariectomy and estradiol in modulating this relationship.
• To explore longitudinal changes in cholinergic function and amyloid beta (Aβ) in elderly humans.

Main Methods:

• Quantification of amyloid beta (Aβ) in male and female App-mutant mice with varying cholinergic tone.
• Assessment of ovariectomy and estradiol replacement effects.
• Longitudinal analysis of basal forebrain cholinergic function and Aβ in elderly individuals.

Main Results:

• A causal link between cholinergic tone and amyloid pathology was identified in males and ovariectomized females.
• This relationship was uncoupled in ovary-intact females and those receiving estradiol replacement.
• In elderly humans, reduced cholinergic function correlated with increased Aβ in both sexes.

Conclusions:

• Findings highlight the importance of considering menopausal status in AD mouse models.
• Therapies targeting estradiol and cholinergic signaling may offer a strategy to reduce Aβ burden in Alzheimer's Disease.