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.
Highlights
Alzheimer’s disease (AD) accounts for 60–80% of total dementia diagnoses (Brookmeyer et al, 2011; Alzheimer’s Association, 2021)
Lau et al (2020b) reported that IL33 injection in an APP/PS1 mouse model resulted in Aβ-plaque-associated microglia acquiring the disease-associated microglia” (DAM) transcriptomic profile with increased levels of Apoe, Axl, Cst7, Lpl, and Trem2 and which was associated with increased clearance of Aβ
Together these findings demonstrate a close relationship between microglial lipid metabolism and phagocytosis
Summary
Alzheimer’s disease (AD) accounts for 60–80% of total dementia diagnoses (Brookmeyer et al, 2011; Alzheimer’s Association, 2021). More recently in AD, microglia have been shown to internalise greater quantities of synaptic material during the symptomatic phase of the disease This has been demonstrated using confocal (Tzioras et al, 2019) and single-molecule localisation microscopy (Paasila et al, 2021) of archival cortical tissue samples. The γ-cleavage site varies in its position and is responsible for the production of Aβ peptides of different lengths, from Aβ37 to Aβ43 (or longer) This is of relevance to AD as Aβ39/40 predominate in cerebral amyloid angiopathy (CAA) (Prelli et al, 1988; Suzuki et al, 1994) and Aβ42/43 in parenchymal deposits (Iwatsubo et al, 1994). Aβ plaques are not sufficient to cause AD, there is a strong association between their formation and the eventual development of AD as demonstrated by rare mutations (including APP, PSEN1, and PSEN2) in familial early- and late-onset AD (Cruchaga et al, 2012; Sassi et al, 2014; Lanoiselée et al, 2017)
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