Adult mouse astrocytes degrade amyloid-β in vitro and in situ

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.

Role of Interleukin-1 in Prion Disease-Associated Astrocyte Activation

“…15 Furthermore, it was recently shown that astrocytes interact directly with amyloid fibrils via scavenger receptors yet to be identified. 38 Thus, the activation of astrocytes may also be promoted by scavenger receptor-mediated signaling as a consequence of the ongoing deposition of misfolded PrP Sc . This activating stimulus could represent a further mechanism to compensate for the absence of IL-1 bioactivity in the IL-1RI Ϫ/Ϫ mice.…”

Astrocytes in Alzheimer's Disease

“…149,150 Functional experiments also demonstrated the ability of astrocytes to phagocyte and degrade ␤-amyloid deposits in an in vitro system. 182 However, these experiments also demonstrated ␤-amyloid sequestration can be done only by astrocytes isolated from healthy brains; the astroglial cells obtained from APP transgenic mice were ineffective. 182 At the same time, the AD conditions may affect astroglia, turning them into A␤ producers.…”

“…182 However, these experiments also demonstrated ␤-amyloid sequestration can be done only by astrocytes isolated from healthy brains; the astroglial cells obtained from APP transgenic mice were ineffective. 182 At the same time, the AD conditions may affect astroglia, turning them into A␤ producers. Production of A␤ requires the endoprotease known as ␤-site APP-cleaving enzyme 1 ([BACE 1] also referred to as ␤-secretase).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…The observation that activated microglia are present at amyloid deposits in human AD and in animal models of this disease suggested that it might play a pathogenic role as a result of their chronic activation, although the presence of cytoplasmic Ab granules in plaque-associated glia and microglia suggest that these cells participate in the clearance of Ab ( [7,42,65,73,125,144,155,180,215,248,254,257,259]). However, this hypothesis is hard to prove using experimental models of this disease in which many pathological features occur, namely amyloid deposition, neurofibrillary tangle formation, inflammation, neuritic and neuronal loss, synaptic and neuronal dysfunction, vascular alterations [197].…”