In a recent translational study published in Alzheimer’s Association Journalresearchers investigated the role of biological sex in the onset and progression of Alzheimer’s disease (AD).
study: Gender-dependent cholinergic effects on amyloid pathology: a translational study. Image credit: Burdun Iliya/Shutterstock.com
Abundant preclinical and clinical data indicate sex-based differences in the pathophysiology of AD. However, murine AD models have primarily focused on male mice, and this gender bias may lead to a lack of translatability to humans.
Nearly two-thirds of late-onset Alzheimer’s disease (LOAD) cases occur in women, who tend to have more severe disease and faster cognitive decline than men. These differences may be due to decreased levels of sex hormones, especially estrogen, during and after menopause.
Therefore, it is of great importance to investigate whether biological sex has a causal effect on the pathology of Alzheimer’s disease.
In relation to AD pathology, various studies using mouse AD models have shown that basal forebrain cholinergic neurons are involved in amyloid beta (Aβ) pathology, a phenomenon that precedes AD-related cortical degeneration and severe dementia. consistently suggest that it is selectively susceptible to.
Researchers also identified a link between decreased cholinergic signaling and increased Aβ levels in the brains of both mouse models and human subjects. Additionally, Aβ interferes with the synthesis and release of acetylcholine (ACh).
To investigate the causal relationship between biological sex, cholinergic signaling, and Aβ pathology, researchers took a translational approach using a mouse AD model.
They developed amyloid precursor protein (App) knock-in (KI) mice that recapitulate the pathophysiology of human Alzheimer’s disease and forebrain vesicular acetylcholine transporter that mimics Alzheimer’s disease-induced basal forebrain cholinergic dysfunction. (VAChT) or mice that overexpress VAChT were bred. .
These experiments were performed separately on male and female mice. For female mice, the researchers also evaluated the effects of surgically induced menopause and estradiol (E2) supplementation.
After being euthanized, the researchers harvested the mice’s brains and used tissue sections from one hemisphere for immunofluorescence. Three to four tissue sections per mouse were used to quantify amyloid burden, defined as the percentage of cortex occupied by amyloid deposits.
Additionally, enzyme-linked immunosorbent assay (ELISA) was performed on the guanidine-insoluble Aβ fraction obtained from cortical extracts. The experimenters were blind to the sex and genotype of the mice throughout collection and analysis.
The study collected data from 58 male and 72 female participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, which focused on individuals aged 70 and over.
Using longitudinal structural magnetic resonance imaging (MRI) data, we tracked changes in forebrain gray matter volume and correlated these changes with brain amyloid quantified with positron emission tomography (PET). I did.
This study revealed a sex-dependent inverse relationship between cholinergic signaling and Aβ pathology in a mouse model of Alzheimer’s disease. The AppNL-F male mouse developed Aβ lesions at approximately 9 months, whereas the AppNL-GF model showed her Aβ deposits much earlier.
Increased VAChT levels reduced Aβ pathology in male mice, but did not have the same effect in female mice with intact ovaries. This sex-specific influence of the cholinergic system on her Aβ pathology was noted.
Cholinergic neurons express E2 receptors, and E2 regulates their function by increasing ACh levels in the basal forebrain and hippocampus. They found that overexpression of VAChT reduced Aβ pathology in ovariectomized female mice, which closely resembles postmenopausal women. This demonstrated how E2 uncouples the relationship between cholinergic signaling and her Aβ pathology in young female mice.
Differences in whole-brain gray matter volume and posterior basal forebrain degeneration between young men and women disappeared in individuals older than 70 years, reflecting the age-dependent effects observed with amyloid PET.
Based on these findings, the researchers emphasized the importance of recreating postmenopausal hormonal status in female AD mouse models to better understand the role of biological sex in AD.
Furthermore, they suggested that treatments targeting E2 and cholinergic signaling may be beneficial in reducing Aβ.
This study specifically demonstrated a bidirectional causal relationship between VAChT levels and Aβ pathology in a murine AD model and highlighted the influence of biological sex on this relationship. However, sex-related differences in Aβ deposition, forebrain atrophy, and this relationship disappeared among humans over more than 70 years.
This study has important implications, especially considering the sexual dimorphism in LOAD risk. Therefore, to more precisely study the pathology of Alzheimer’s disease, it is necessary to reproduce the hormonal status of postmenopausal women in mice.
Because E2 disrupts the relationship between VAChT levels and Aβ pathology, there is a potential risk that hormone replacement therapy (HRT) may interfere with the benefits of cholinesterase inhibitors (ChEIs) prescribed for AD treatment.
Therefore, further research on the effects of HRT on ChEIs is important to enhance treatment efficacy, adjust dosage, and differentiate between responsive and non-responsive AD patients.
Liliana German-Castellan, Haley RC Shanks, Robert Gross, Takashi Saito, Takaomi C. Sides, Lisa M. Saxida, Timothy J. Bussey, Marco A. M. Prado, Taylor W. Schmitz, Vania・F. Prado, (2023) Sex-dependent cholinergic influence on amyloid pathology: a translational study, Australian Imaging Biomarkers and Lifestyle Aging Flagship Study, Alzheimer’s Association Journal. Doi: https://doi.org/10.1002/alz.13481. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13481