. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017 Dec 20;552(7685):355-361. PubMed.


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  1. Based on the identification of full-length Aß42 and N-terminally heterogeneous Aß42 as the main Aß species in amyloid plaques isolated from patients with sporadic Alzheimer’s disease, we have postulated that Aß42 is a key player in AD pathogenesis. Indeed, more recent data confirm that Aß42 species are dominant in the Alzheimer’s disease brain, that it takes 19 years to accumulate amyloid from threshold PET uptake value ratio to the mean value observed for AD dementia, and that the 4.8 mg difference between Alzheimer’s disease and control brain corresponds to an Aß42 accumulation of 28 ng/h (Roberts et al., 2017). The findings from Venegas et al. complement this research by demonstrating that approximately 40–50 percent of these 28 ng/h are controlled by microglia-derived ASC specks. Apoptosis-associated speck-like protein assemblies—ASC specks—undergo a prion-like polymerization upon activation of inflammasome sensors and form large protein complexes reaching a size of around 1 μm, well-suited for simple readout of its role in Aß pathogenesis (Lu et al., 2014).

    As shown by Venegas et al., Aß deposition in AD activates inflammasome-dependent formation of ASC specks in microglia and leads to their subsequent release. In hippocampal sections of AD brains, the majority of ASC specks are detected outside of microglia and the extracellular ASC specks are co-localized with the Aß42 plaques. In APPswePSEN1dE11 mice crossed with ASC-/-, at eight months of age the number of Aß deposits is reduced to half of what is observed for PPswePSEN1dE11 mice. Co-injection of anti-ASC antibodies with APPswePSEN1dE11 brain lysates of eight-month-old mice into three-month APPswePSEN1dE11 mice resulted in approximately 40–50 percent reduction in total number of Aß deposits, again most likely Aß42 aggregates, after five months. Since in these injection experiments relative phagocytosis and levels of the Aß-degrading proteases IDE, NEP, and CASP-1 remained grossly unaltered, degradation of Aß42 is unlikely to account for the observed blocked increase in Aß42 deposition in APPswePSEN1dE11 mice.

    Are ASC specks then the hitherto missing co-factor for efficient induction of Aß42 plaque formation with synthetic Aß? Given the same effect that extracellular ASC speck has in vitro and in vivo on Aß40 and on Aß42 aggregation, and the highly different aggregation properties of both Aß species in vivo (McGowan et al., 2005), it is more likely that the ASC speck interactions influence the equilibrium between non-aggregating, α-helical or unfolded forms of Aß and the aggregation-prone, ß-structure form of Aß. One remaining question is why does Aß40 not form amyloid plaques in the presence of ASC spots? And another question might be whether intracellular ASC-Aß42 complexes form a nidus for other types of aggregates which result in the formation of neurofibrillary tangles and neurites (He et al., 2017). 


    . Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET. Brain. 2017 May 1;140(5):1486-1498. PubMed.

    . Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 2014 Mar 13;156(6):1193-1206. PubMed.

    . Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-199. PubMed.

    . Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018 Jan;24(1):29-38. Epub 2017 Dec 4 PubMed.

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