Abstract
Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by brain atrophy, amyloid plaques, intracellular neurofibrillary tangles, and neuroinflammation (Braak and Braak, 1991; Jack et al, 1998; Heppner et al, 2015)
Aβ fibrils made in vitro do not efficiently induce amyloid plaque formation when injected into the hippocampus of young AD model mice, whereas brain extracts from AD patients and aged AD model mice lead to Aβ deposition into plaques (Meyer-Luehmann et al, 2006)
Evidence from this study suggests that LC3associated endocytosis (LANDO) facilitates recycling of the Aβ receptors CD36, TLR4 and triggering receptor expressed on myeloid cells 2 (TREM2), allowing cycles of Aβ endocytosis to continue, promoting Aβ uptake and clearance (Heckmann et al, 2019)
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by brain atrophy, amyloid plaques, intracellular neurofibrillary tangles, and neuroinflammation (Braak and Braak, 1991; Jack et al, 1998; Heppner et al, 2015). Stimulation of the murine microglial cell line BV-2 with TLR2 and TLR4 ligands significantly increased the internalization of Aβ in vitro, further implicating TLR receptors in Aβ uptake and clearance (Tahara et al, 2006; Song et al, 2011) Another family of receptors found to be involved in the internalization of Aβ fibrils are the scavenger receptors (SRs), which are highly expressed by microglia (Christie et al, 1996; Wilkinson and El Khoury, 2012). CD36 is a class B scavenger receptor identified to form a receptor complex with the α6β1-integrin and the integrin-associated protein CD47 in microglia This complex was shown to mediate the binding of Aβ fibrils to microglial cells and the subsequent activation of intracellular signaling pathways (Bamberger et al, 2003). Together this evidence suggests that Aβ is a ligand for TREM2, and that TREM2 has a role to play in both Aβ clearance and Aβ-stimulated microglial activation
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