Interplay Between Microglia and Alzheimer’s Disease—Focus on the Most Relevant Risks: APOE Genotype, Sex and Age

Abstract

As the main immune cells of the central nervous system (CNS), microglia regulates normal development, homeostasis and general brain physiology. These functions put microglia at the forefront of CNS repair and recovery. Uncontrolled activation of microglia is related to the course of neurodegenerative diseases such as Alzheimer’s disease. It is clear that the classic pathologies of amyloid β (Aβ) and Tau are usually accompanied by the activation of microglia, and the activation of microglia also serves as an early event in the pathogenesis of AD. Therefore, during the occurrence and development of AD, the key susceptibility factors for AD—apolipoprotein E (APOE) genotype, sex and age—may further interact with microglia to exacerbate neurodegeneration. In this review, we discuss the role of microglia in the progression of AD related to the three risk factors for AD: APOE genotype, sex and aging. APOE-expressing microglia accumulates around Aβ plaques, and the presence of APOE4 may disrupt the phagocytosis of Aβ aggregates and aggravate neurodegeneration in Tau disease models. In addition, females have a high incidence of AD, and normal female microglia and estrogen have protective effects under normal conditions. However, under the influence of AD, female microglia seem to lose their protective effect and instead accelerate the course of AD. Aging, another major risk factor, may increase the sensitivity of microglia, leading to the exacerbation of microglial dysfunction in elderly AD. Obviously, in the role of microglia in AD, the three main risk factors of APOE, sex, and aging are not independent and have synergistic effects that contribute to the risk of AD. Moreover, new microglia can replace dysfunctional microglia after microglial depletion, which is a new promising strategy for AD treatment.

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“…While LOAD has not a well-established etiology, two of the most relevant genes conferring a significantly risk factor are the E4 apolipoprotein allele (APOEε4) and the triggering receptor expressed on myeloid cells 2 (TREM2) [ 8 , 9 , 10 ]. The ε4 allele of the APOE gene codes for the main apolipoprotein of the CNS, whose functions are lipid transport and neuron homeostasis [ 8 , 9 , 10 , 11 , 12 ]. It has been reported that one copy of the ε4 allele in APOE increases LOAD risk by 3~4-fold [ 10 , 11 ].…”

“…On the contrary, carriers of the APOEε2 allele have two times less risk of suffering from LOAD than non-carriers, being considered a protective genetic factor against this disease [ 12 ]. There are significant clinical and basic evidence that shows early driving amyloid pathology in the brains of APOEε4 carriers [ 8 , 9 , 10 ]. Furthermore, in several brain homeostatic pathways, including lipid transfer, synaptic integrity and plasticity, glucose metabolism and cerebrovascular activity, APOE4 is either pathogenic or a decreasing factor of performance [ 8 , 9 , 10 , 11 ].…”

“…There are significant clinical and basic evidence that shows early driving amyloid pathology in the brains of APOEε4 carriers [ 8 , 9 , 10 ]. Furthermore, in several brain homeostatic pathways, including lipid transfer, synaptic integrity and plasticity, glucose metabolism and cerebrovascular activity, APOE4 is either pathogenic or a decreasing factor of performance [ 8 , 9 , 10 , 11 ]. In turn, TREM2 is a very abundant receptor on the surface of microglia and plays an important role in its activation and regulation [ 13 , 14 ].…”

“…A retrospective study of 20 prospective clinical trials concluded that the prevalence of LOAD in patients with T2DM was 56% greater than in people without diabetes [ 21 ]. Brain insulin resistance, decreased insulin signaling, inflammation, hyperglycemia, vascular alterations, hypoglycemic events, and impaired amyloid metabolism are proposed causes for this relationship [ 9 ]. Consequently, it has been shown that both T2DM and LOAD possess multifactorial risk profiles and a wide variety of molecular connections.…”

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

“…Microglial cells, or microglia, represent resident immune cells of the cerebral parenchyma, and, alongside perivascular macrophages, belong to the innate immune system [ 16 , 17 , 18 ]. These are the only glia that have a myeloid origin, developing from the extraembryonic yolk sac exclusively during a surprisingly restricted interval [ 19 , 20 ].…”