Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease

Abstract

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPPSEN1 mice. By contrast, homogenates from brains of APPPSEN1 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPPSEN1 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPPSEN1 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

“…Elegant work demonstrated that aggregated Aβ displaying amyloid structure [38, 55] activates the NLRP3–ASC inflammasome, following endo-lysosomal uptake and damage [38], resulting in the activation of caspase-1, subsequent cleavage of pro-IL-1β to IL-1β, and microglial activation [38]. NLRP3 inflammasome assembly was subsequently demonstrated to actively contribute to amyloid pathology [42, 95]. Heneka et al elegantly demonstrated that inflammasome inhibition through NLRP3 or caspase-1 deficiency inhibits amyloid pathology in APP/PS1 transgenic mice [42, 95], with alterations in microglial phenotypes and phagocytosis capacity as potential contributing mechanisms.…”

“…NLRP3 inflammasome assembly was subsequently demonstrated to actively contribute to amyloid pathology [42, 95]. Heneka et al elegantly demonstrated that inflammasome inhibition through NLRP3 or caspase-1 deficiency inhibits amyloid pathology in APP/PS1 transgenic mice [42, 95], with alterations in microglial phenotypes and phagocytosis capacity as potential contributing mechanisms. These findings were further confirmed using pharmacological NLRP3 inhibitors [16, 19].…”

“…This is particularly interesting in the context of prion-like propagation in AD and related neurodegenerative disorders. Venegas et al demonstrated that aggregation of ASC into prion-like ASC specks exacerbated amyloid pathology [95], by a cross-seeding mechanism. While the relation between Aβ and inflammasome has been analyzed in exquisite detail, the relation between inflammasome and Tau and prion-like propagation of Tau pathology remains unexplored.…”

“…A crucial role for NLRP3–ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3–ASC inflammasome (Halle et al in Nat Immunol 9:857–865, 2008) and conversely NLRP3–ASC inflammasome activation exacerbates amyloid pathology in vivo (Heneka et al in Nature 493:674–678, 2013), including by prion-like ASC-speck cross-seeding (Venegas et al in Nature 552:355–361, 2017). However, the link between inflammasome activation, as crucial sensor of innate immunity, and Tau remains unexplored.…”

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B₁

“…The role of microglia in CNS development is clear due to the fact that the CNS incorporates several disintegrations in the case of malfunctioning of the mutation-induced microglial cells [12, 13]. As CNS-resident macrophages have many features of innate immune responses, such as the secretion of pro- and anti-inflammatory cytokines, nitric oxide, and expression of many receptors (i.e., TLRs) [14], microglia are involved in nearly all CNS diseases in which we could see inflammation or degeneration, such as Alz­heimer’s disease [15], multiple sclerosis [16], and Parkinson diseases [17]. …”