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Alzheimer disease is characterized by the presence of amyloid-β (Aβ) plaques in the brain (which are thought to cause neuronal dysfunction), as well as by neurochemical changes and inflammation. Writing in Nature, Venegas and colleagues found that aggregates of apoptosis-associated speck-like protein containing a CARD (ASC), which result from innate immune activation, can seed Aβ deposition. Interfering with ASC specks reduced Aβ deposition in a mouse model of Alzheimer disease.

Activation of the innate immune system is an early occurrence in numerous neurodegenerative diseases. Aberrant or misfolded proteins can be recognized by microglial pattern recognition receptors, resulting in the activation of NOD-, LRR- and pyrin domain-containing 3 (NLRP3), a component of the inflammasome. This molecule recruits ASC, which assembles into large helical fibrils, and promotes the production and release of proinflammatory cytokines.

purified ASC specks ... increased the deposition of Aβ

Although Aβ can activate NLRP3, innate immune activation can precede Aβ production, prompting the authors to examine the contribution of NLRP3 activation to Aβ plaques. Furthermore, synthetic Aβ itself does not form plaques efficiently, suggesting that a cofactor is required for Aβ assembly and deposition. Indeed, purified ASC specks accelerated aggregation of both of the forms of Aβ that are thought to be pathogenic (Aβ1–40 and Aβ1–42), suggesting that ASC specks seed Aβ aggregates. This aggregation was dependent on three amino acids within the pyrin domain of ASC, which likely interact directly with Aβ.

In a mouse model of Alzheimer disease (APP/PS1 mice), ASC co-immunoprecipitated with Aβ in brain lysates, particularly in aged mice. These proteins were not found together in the brains of wild-type mice. Immunohistochemistry confirmed this observation; even in the brains of presymptomatic mice, protein structures with an ASC core surrounded by Aβ were observed. Similarly, ASC–Aβ complexes were found in the brains of patients with Alzheimer disease, including those with early forms, but not in the brains of patients with other neurodegenerative diseases.

Aged APP/PS1;Asc−/− mice had reduced levels of cerebral Aβ and improved spatial memory compared with APP/PS1 mice. Injection of APP/PS1 brain lysates into the brains of APP/PS1 mice, but not into APP/PS1;Asc−/− mice, increased Aβ deposition, suggesting a role for endogenous ASC in this process. Thus, ASC specks could seed Aβ deposition, which then promotes further ASC speck formation through the activation of the innate immune system.

Reducing the interaction between ASC specks and Aβ reduced Aβ spreading. If APP/PS1 mice received a co-injection of an antibody specific to ASC specks along with the APP/PS1 brain homogenates, the Aβ monomers and oligomers were reduced.

These results show that the NLRP3 inflammasome and its downstream activator, ASC, are key components in the development of Alzheimer disease. Targeting inflammasome components, particularly in the early stages of disease, could slow the formation of Aβ plaques and thus delay the neurological sequelae in these patients.