The X factor in neurodegeneration

Abstract

Given the aging population, it is important to better understand neurodegeneration in aging healthy people and to address the increasing incidence of neurodegenerative diseases. It is imperative to apply novel strategies to identify neuroprotective therapeutics. The study of sex differences in neurodegeneration can reveal new candidate treatment targets tailored for women and men. Sex chromosome effects on neurodegeneration remain understudied and represent a promising frontier for discovery. Here, we will review sex differences in neurodegeneration, focusing on the study of sex chromosome effects in the context of declining levels of sex hormones during aging.

Figure 1.

Sex hormone and sex chromosome effects. Age-related changes in sex hormones (estrogen versus testosterone) in the context of sex chromosome (XX versus XY) effects across the lifespan. Estrogen, red; testosterone, blue; sex chromosomes, green.

Figure 2.

FCG mice. The Y chromosome gene that encodes for testicular development (Sry) is deleted, with mice designated XY−. Both XX and XY− mice are ovary-bearing (red). Comparisons between XX versus XY− mice sharing a common gonadal type (females throughout life) reveal sex chromosome effects. When the Sry transgene is added back at an autosomal location, designated Sry, both XX Sry and XY− Sry mice are testes bearing (blue). Comparisons between XX Sry versus XY− Sry mice sharing a common gonadal type (males throughout life) also reveal sex chromosome effects. Comparisons between mice with a common sex chromosome complement, with or without the Sry gene, reveal sex hormone effects (ovary bearing versus testes bearing throughout life). Comparisons between mice with a common sex chromosome complement that are gonadectomized reveal developmental (organizational) effects of sex hormones (not shown).

Figure 3.

Bedside to Bench to Bedside to study sex differences in neurodegeneration: Region-specific, cell-specific, and sex-specific research. Clinical observations of sex differences are investigated at the preclinical level and then translated back to the clinic as trials designed for each sex. Bench investigations entail in vivo MRI for region-specific atrophy, neuropathology of each region, RNA sequencing of each CNS cell from each region, immunohistochemistry validation of genes in top differentially expressed pathways, knockout of target gene in each CNS cell (CKO) to reverse phenotype, and knockdown of target gene with pharmacologic treatment (Tx) to reverse phenotype. Reiteration can determine the effect of genetic (CKO versus WT) and/or pharmacologic (treatment versus placebo) intervention on reversal of gene expression using the same cell-specific and region-specific approach in each sex. Also, replacement of female versus male mice in the beginning with gonadectomized versus gonadally intact mice will reveal activational effects of sex hormones, while FCG mice will reveal developmental hormone effects or sex chromosome effects, each in a region-specific and cell-specific manner.