Amyloid-β-Induced Astrocytic Phagocytosis is Mediated by CD36, CD47 and RAGE

Abstract

Astrocytes, the most numerous glial cell in the brain, have multiple functions and are key to maintenance of homeostasis in the central nervous system. Microglia are the resident immunocompetent cells in the brain and share several functions with macrophages, including their phagocytic ability. Indeed microglia are the resident phagocytes in the brain and express numerous cell surface proteins which act to enable receptor-mediated phagocytosis. However recent evidence suggests that astrocytes express some genes which permit phagocytosis of phosphatidylserine-decorated cells and this probably explains sporadic reports in the literature which suggest that astrocytes become phagocytic following brain trauma. Here we examined the potential of astrocytes to phagocytose fluorescently-labelled latex beads and amyloid-β (Aβ) and report that they competently engulf both in a manner that relies on actin polymerization since it was inhibited by cytochalasin D. The data indicate that incubation of cultured astrocytes or microglia with Aβ increased phagocytosis and markers of activation of both cell types. Aβ was found to markedly increase expression of the putative Aβ-binding receptors CD36 and CD47 in astrocytes, while it decreased expression of the receptor for advanced glycation endproducts (RAGE). It is demonstrated that blocking these receptors using a neutralizing antibody attenuated Aβ-induced phagocytosis of latex beads by astrocytes. Interestingly blocking these receptors also decreased uptake of beads even in the absence of Aβ. Here we demonstrate that astrocytes are competent phagocytes and are capable of engulfing Aβ.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…Supporting a phagocytic role for reactive astrocytes in AD, it has been suggested that they could mediate Aβ clearance (Osborn et al, 2016) and limit amyloid deposits (Xiao et al, 2014) since these glial cells express many potential phagocytic receptors that bind Aβ (Jones, Minogue, Connor, & Lynch, 2013; Sokolowski & Mandell, 2011). Moreover, astrocytes in culture are highly phagocytic cells (Roldán, Gogg, Ferrini, Schillaci, & De Nicola, 1997; Tansey & Cammer, 1998), and can phagocytose Aβ (Wyss‐Coray et al, 2003) and apoptotic cells (Chang, Barbaro, & Pieper, 2000) and effectively engulf whole dead cells following neural scratch injury in vitro (Lööv, Hillered, Ebendal, & Erlandsson, 2012).…”

Astrocyte roles in traumatic brain injury

“…Stimulation of astrocyte pattern recognition receptors by DAMPs results in nuclear-factor-κB (NFκB) signaling, the production of proinflammtory cytokines like tumor necrosis factor α (TNFα), α-chemokines, as well as inflammatory mediators cyclooxygenase-2 and matrix metalloproteinase 9 (MMP-9) (Pedrazzi et al, 2007; Ponath et al, 2007; Gorina et al, 2011). Intriguingly, amyloid-β mediated activation of astrocyte RAGE stimulates astrocytes themselves to become phagocytic and engulf extracellular amyloid-β (Jones et al, 2013), possibly implicating reactive astrocytes in the clearance of neuro- and gliotoxic amyloid protein after injury. Additionally, pathogen-associated molecular patterns (PAMPs) from bacterial pathogens, such as lipopolysaccharide also bind astrocyte pattern recognition receptors and elicit expression of immunomodulatory and pro-inflammatory molecules (Hoarau et al, 2011; Hamby et al, 2012).…”

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

“…Reactive astrocytes are phagocytic cells that are able to ingest dead cells, neuronal synapses, and protein aggregates of Aβ and α-synuclein [18][19][20][21][22]. Especially in early stages of AD, astrocytes appear to be even more efficient than microglia in engulfing Aβ [22].…”