Synapses, Microglia, and Lipids in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.

Keywords: APOE; Alzheimer’s disease; TREM2; lipids; microglia; synapses.

FIGURE 1

Microglial rod cells rich in lipoid material (scarlet red staining; Sudan IV). Drawing taken from Spielmeyer (1922).

FIGURE 2

Under physiological conditions TREM2 facilitates the phagocytosis of APOE-lipoprotein-bound Aβ. Lipid molecules are processed by the intracellular phagolysosomal system to yield free cholesterol which may be stored internally as cholesteryl esters or secreted by ATP-binding cassette (ABC) transporters. Aβ may be degraded in autophagic vacuoles, via the ubiquitin-proteasomal system, or by any of a number of Aβ-degrading proteases including the metalloendopeptidase and matrix metalloproteinase families of catabolic enzymes. Furthermore, DAP12 activation following TREM2 binding results in the activation of the PI3K/AKT/mTOR signalling cascade which reduces the secretion of signalling molecules such as IL1β, IL6, and TNFα which in turn is associated with reduced activation of intraneuronal GSK3β—an important protein kinase responsible for tau phosphorylation and which is also involved in the activation of γ-secretase through its interaction with presenilin 1. The R47H loss of function mutation in TREM2 and the APOE ε4 allele (both indicated in red) represent two factors which impair Aβ and lipid processing by microglia. Abnormal TREM2/DAP12 signalling may result in reduced PI3K/AKT/mTOR signalling and disinhibition of IL1β, IL6, and TNFα secretions, leading to increased intraneuronal phosphotau and the exacerbation of Aβ accumulation (indicated by the red arrows). Created with BioRender.com.

FIGURE 3

Age-related myelin degeneration and dyslipidemia represent two risk factors for the accumulation of saturated fats and other lipids in the brain. These lipids may be internalised by microglia and stored as cholesteryl esters. Lipid-droplet-accumulating microglia (LDAM) accumulate with age and are associated with increased secretion of IL1β, IL6, TNFα, complement molecules, and show impaired maturation of phagosomes and reduced phagocytic capacity. As demonstrated in Figure 2, the increased secretion of certain cytokines and impaired phagocytosis are linked with more severe neuropathological changes. The signalling cytokines are also implicated in the activation of oligodendrocytes (which may be a source of excess complement deposition) and the neurotoxic activation of astrocytes (for which saturated fats are a sufficient driver). Increased expression and deposition of complement proteins may represent a key event in the targeting of synapses by microglia in AD. Created with BioRender.com.

FIGURE 4

Amyloid plaque stained using the Herxheimer technique (Sudan IV). Significant amounts of lipids are found inside the plaque and in neighbouring glial cells. One cell probably representing a microglial cell is shown in the lower right. Formalin-fixed brain tissue, frozen section. Photograph taken by the authors (MBG): 20× oil primary magnification. Tissue section from Alois Alzheimer’s laboratory (Alzheimer, 1911; Graeber et al., 1997).