Heckmann BL, Teubner BJ, Boada-Romero E, Tummers B, Guy C, Fitzgerald P, Mayer U, Carding S, Zakharenko SS, Wileman T, Green DR. Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Sci Adv. 2020 Aug;6(33):eabb9036. Epub 2020 Aug 14 PubMed.

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  1. Commonly employed mouse models of Alzheimer’s disease (AD) are almost exclusively driven by transgenic expression of known genetic modifiers of the disease. In this study, Heckmann et al. present an exciting new model where a subtle change in the domain composition of the autophagy gene ATG16L (ATG16L∆WD) leads to spontaneous Aβ deposition, tau pathology, and neuronal degeneration in the absence of any AD-related pathological protein overexpression.

    To demonstrate that the findings in this model are consistent with human disease biology, the authors also show a decrease in ATG16L and other LC3-associated endocytosis (LANDO) proteins in the brains from a small cohort of AD patients. This encouraging finding will be critical to reproduce in larger, diverse cohorts of AD patients. Overall, although ATG16L∆WD is sufficient to endogenously lead to AD pathologies in mice, the relevance of this finding to AD patients more broadly remains an open question. Should these findings in human samples be substantiated through additional work in larger cohorts, this model could be of significant interest to the field. It may better represent aspects of human disease and would not be as uniformly driven by Aβ levels or prone to the APP overexpression artifacts observed in other models.

    The authors propose that neuronal death in this model is driven by a robust pro-inflammatory microglial response. Based on this hypothesis, they examine the efficacy of a brain-penetrant NLRP3 inhibitor, MCC950, which reduced pro-inflammatory cytokine IL-1β and p-tau levels, and rescued behavioral endpoints. Interestingly, MCC950 treatment did not alter amyloid levels contrary to previous data in a different AD model (Dempsey et al., 2017), highlighting the challenges associated with the utilization of a range of preclinical models to study a complex disease. The robust cytokine alterations observed in this model have also not yet consistently been seen in the CNS of AD patients, but it is possible patients who would benefit from NLRP3 inhibitors could be identified by more detailed analysis of biomarkers such as IL-1β. These studies would be extremely helpful in more conclusively determining the potential benefit of NLRP3 for treatment of AD.

    In order to investigate the mechanisms underlying the microglia activation, Heckmann et al. investigated the expression of AD-relevant cell-surface receptors such as Trem2 on primary microglia and found they were reduced. This led to decreased Aβ uptake using in vitro assays, but this mechanism was not investigated nor validated in vivo. Though intriguing, this mechanistic link between ATG16L∆WD, Aβ uptake, and inflammasome activation requires further study.

    Overall, the potential link between autophagy and AD-relevant phenotypes is an interesting one, especially as ATG16L function appears most relevant in microglia rather than neurons or other CNS cell types. However, as this is not a genetic variation that has been directly associated with increased risk of AD, additional work is required to determine whether the authors have identified an exciting disease-relevant pathway or a genetic alteration that results in similar downstream phenotypes.

    References:

    Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson AA, Cooper MA, O'Neill LA, Lynch MA. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017 Mar;61:306-316. Epub 2016 Dec 18 PubMed.

    View all comments by Lesley Kane

  2. We have developed mouse models that accumulate Aβ without overexpressing APP or APP/PS1 (Saito et al., 2014). They are being used by more than 400 laboratories world-wide, so overexpression artifacts are not always a problem with AD models.

    Still, in our models, more than 30 percent coverage of the cerebral cortex by Aβ did not induce any neurodegeneration even after 18 months (Masuda et al., 2016). The primary question to ask is thus, how does Aβ deposition induce tau pathology and neurodegeneration over decades during preclinical AD? In other words, AD pathology is a biology of time, which is often underappreciated.

    References:

    Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

    Masuda A, Kobayashi Y, Kogo N, Saito T, Saido TC, Itohara S. Cognitive deficits in single App knock-in mouse models. Neurobiol Learn Mem. 2016 Nov;135:73-82. Epub 2016 Jul 1 PubMed.

    View all comments by Takaomi Saido

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  1. Can Loss of a Single Protein Domain Cause ‘Alzheimer’s’ in Mice?

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  1. Atg16LΔWD