Modulation of β-Amyloid Fibril Formation in Alzheimer's Disease by Microglia and Infection

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.

Keywords: Alzheimer’s disease; Aβ; amyloid fibril; amyloid plaques; infection; microglia; β-amyloid.

FIGURE 1

Modulation of Aβ amyloid fibril assembly and clearance by microglial cells and infection, and potential targets of intervention. Aβ peptide assembles into highly ordered amyloid fibrils with a characteristic cross-β structure. These fibrils form the core of amyloid plaques present in AD brains. Microglia surround these plaques, forming a protective barrier around them, limiting the recruitment of further Aβ. Microglia can also contribute to the clearance of Aβ fibrils. In order to remove Aβ deposits in AD, the phagocytic activity of microglia could be enhanced by targeting receptors and pathways involved in this response, such as TREM2 and CD33. Increasing the breakdown by microglial proteases could also enhance clearance of Aβ deposits. The NLRP3 inflammasome in microglia is concurrently activated in response to Aβ fibrils, resulting in the release of ASC specks. These specks cross-seed the formation of Aβ fibrils, resulting in further Aβ aggregation. Therefore, inhibiting the activation of the NLRP3 inflammasome would reduce the cross seeding of Aβ aggregation by ASC specks. Aβ also has antimicrobial and antiviral-properties, assembling into amyloid fibrils in response to infection. Thus, infection could be targeted to reduce Aβ aggregation.

FIGURE 2

Mechanism of NLRP3 activation by amyloid fibrils. A priming signal, such as LPS, leads to the increased expression of NLRP3 and precursor forms of inflammatory cytokines IL-1β and IL-18. Aβ fibrils act as an activating stimulus via their internalization and disruption of lysosomes leading to the release of cathepsin B into the cytosol. This is thought to trigger the assembly of the NLRP3 inflammasome complex. This complex recruits ASC adaptor protein, which forms filaments. ASC filaments interact with pro-caspase 1 via CARD domains, resulting in caspase-1 activation. Active caspase 1 cleaves precursor forms of IL-1β and IL-18, which are secreted from immune cells in their active form, contributing to neuroinflammation. Caspase 1 also cleaves gasdermin D, which forms pores in the cell membrane, eventually resulting in pyroptotic cell death.

FIGURE 3

ASC specks released from activated microglia cross-seed Aβ aggregation. The NLRP3 inflammasome is activated in microglia in response to a variety of stimuli, including Aβ fibrils. This activation leads to the release of specks formed from ASC, an adaptor protein that is involved in the inflammasome pathway. ASC specks cross-seed Aβ peptide, resulting in the formation of further Aβ aggregates in the brain and may create a cycle of inflammasome activation and amyloid formation.