Sex Differences in Alzheimer’s Disease, Immune Response and Microglia

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is associated with age. AD has been increasingly prevalent affecting more women than men. In addition to age, sex differences are also thought to contribute to AD prevalence as genes can be expressed in a sex dependant manner and the sex hormones are thought to drive sex differences in gene expression and immune cell function. Microglia are the main immunocompetent cell of the brain. Their functions allow them to survey the brain constantly and play a role in the maintenance of neurons and the synapses. Phagocytosis is one of the primary immune functions of microglia as they are involved in synaptic pruning and clearance of neuronal debris. Proinflammatory responses are also carried out by microglia when stimulated by proinflammatory triggers such as lipopolysaccharides (LPS) and can also be activated by proteins and environmental factors that trigger similar pathways as pathogenic stimuli (such as LPS). Studies investigating immunometabolism of microglia revealed that microglia proinflammatory responses drive microglia to a more glycolytic state whereas anti- inflammatory or unstimulated microglia tend to favour oxidative phosphorylation. Sex differences are thought to play a role in the immune system. Previous studies demonstrated that there are sex differences in gene expression and function between male and female immune cells. The sex hormones oestrogen and testosterone were also observed to play a role in the immune system. Moreover, oestrogen is thought to more immunoenhancing in low doses and immunosuppressive in high doses. However, testosterone is thought to be immunosuppressive despite the dose. Sex differences in AD were also observed in previous studies, sex differences were observed in the mutation of APOE and was suggested to play a role in the risk for AD. Sex hormones were also demonstrated to be involved as the levels of oestrogen were observed to play a role in the risk for AD. Reduced oestrogen levels were associated with a twofold increase in risk in AD. Taken together, the role of sex differences were investigated in AD and existing literature provide evidence on the influence of sex differences and hormones on the immune system, microglia and AD. However, there is still much to be uncovered as more investigations are required to understand how and when are microglia affected by sex differences as AD progression is suggested to occur early before menopause and continue to develop even after therefore further elucidation as to why this occurs is needed. Perhaps immunometabolism of microglia could play a role in the detrimental immune responses of microglia therefore investigations into sex differences in the metabolism of microglia could give an insight into the possibility of an impact on microglial metabolism by sex differences.