One family of receptors involved in the immune response to Aβ amyloid are the Toll-like receptors (TLRs) a class of pattern recognition receptors that recognize conserved microbial structures (Kawasaki and Kawai, 2014). TLRs are type I integral membrane proteins which recognize ligands with their leucine-rich repeat (LRR)-containing ectodomains. RNA sequencing revealed that the expression of six TLR genes (1,2,4,5,6,8) is upregulated in the temporal cortex of AD patients when compared to control brains, likely resulting from increased microglial activation (Chakrabarty et al., 2018). A direct interaction was identified between Aβ fibrils and CD14, a TLR co-receptor previously shown to associated with the inflammatory response to fibrillar Aβ (Fassbender et al., 2004; Reed-Geaghan et al., 2009). This interaction was shown to facilitate the internalization of Aβ fibrils by microglia, at lower concentrations than that required for cell activation (Liu et al., 2005). This suggests that CD14 could be involved in the phagocytosis of Aβ fibrils at low concentrations, but increased Aβ levels in AD results in cellular activation. Consistent with a role in Aβ uptake, TLR4 deficiency in AD mouse models results in increased fibrillar and soluble Aβ deposition (Tahara et al., 2006). Conversely, 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).

which are highly expressed by microglia (Christie et al., 1996; Wilkinson and El Khoury, 2012). It was found initially that class A SRs, characterized by an extracellular collagen-like domain, are involved in the binding to Aβ fibrils to microglial cells (El Khoury et al., 1996). It was then shown that coincubation of microglia with SR ligands such as acetyl-low density lipoprotein (Ac-LDL) reduced Aβ uptake, and CHO cells transfected with class A, or class B SR's showed enhanced Aβ uptake, suggesting that SRs are important in the uptake and clearance of Aβ (Paresce et al., 1996). Further investigation using microglia that are deficient in SR-A1 confirmed the role of SR-A1 and also SR-B1 in binding Aβ fibrils, consistent with a role in the clearance of Aβ amyloid (Husemann et al., 2001). 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). While initial studies reported that Aβ fibril binding to this complex is largely involved in the activation of an inflammatory response, it was also reported that the interaction of Aβ fibrils with this complex is involved in the phagocytic uptake of fibrils by microglia (Coraci et al., 2002; Moore et al., 2002; Bamberger et al., 2003; Koenigsknecht and Landreth, 2004).

The deletion of TREM2 in primary microglia was shown to significantly reduce the phagocytosis of aggregated Aβ1–42 (Kleinberger et al., 2014). Similarly, TREM2 deficiency reduced the efficacy of antibody-targeted Aβ phagocytosis by microglia (Xiang et al., 2016). There is evidence for direct interactions between TREM2 and Aβ1–42 fibrils, although no difference in binding affinity was identified for TREM2 R47H and R62H variants that are associated with an increased risk of AD (Lessard et al., 2018). However, the internalization of monomeric Aβ was reduced with the expression of these TREM2 AD variants (Lessard et al., 2018). In another study, TREM2 was found to bind to Aβ oligomers with a similar affinity to previously described Aβ receptors, CD36 and receptor for advanced glycation end products (RAGE), and this interaction was compromised by R47H and R62H TREM2 mutations (Zhao et al., 2018). In this study, TREM2 deficiency had little effect on Aβ uptake but led to significantly reduced Aβ degradation once internalized by microglia (Zhao et al., 2018). In TREM2 knock out mice injected with Aβ oligomers, there was reduced microglial migration to the site of injection and reduced Aβ clearance (Zhao et al., 2018). A recent study found that loss of TREM2 function led to an acceleration in early amyloidogenesis, accompanied by a reduction in microglial recruitment as previously described, again suggesting that TREM2 has a role in microglial clearance of Aβ (Parhizkar et al., 2019). 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.

Evidence from this study suggests that LANDO facilitates recycling of the Ab receptors CD36, TLR4 and TREM2, thus allowing cycles of Ab endocytosis to continue,
promoting Ab uptake and clearance (Heckmann et al., 2019).

The autophagy proteins ATG5 and Rubicon were found to be protective against Ab deposition, with their absence leading to increased pathology. The expression of autophagy proteins declines with age, which may be related to the development of
Ab pathology in AD (Rubinsztein et al., 2011). It is important to note that macroautophagy has previously been implicated in the secretion of Ab into the extracellular space where it forms plaques in AD (Nilsson et al., 2013). When autophagyrelated gene 7 (ATG7) was conditionally knocked out in excitatory neurons of APP transgenic mice, extracellular Ab plaque pathology was significantly decreased, and Ab instead accumulated intracellularly (Nilsson et al., 2013). Thus, a
reduction in expression of proteins involved in macroautophagy could affect both Ab secretion and clearance.