Microglia use TAM receptors to detect and engulf amyloid β plaques

Huang, Youtong; Happonen, Kaisa E.; Burrola, Patrick; O’Connor, Carolyn; Hah, Nasun; Huang, Ling; Nimmerjahn, Axel; Lemke, Greg

doi:10.1038/s41590-021-00913-5

Cited by 252 publications

(248 citation statements)

References 61 publications

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“…Indeed, recent studies demonstrated that sustained depletion of microglia in the 5XFAD model impaired plaque development, revealing a central role of reactive microglia in genesis of Aβ plaques ( 43 ). Moreover, microglia were found to promote dense-core plaques via phagocytic uptake of loosely organized Aβ and condensing it into dense deposits in lysosomes ( 53 ). It would be interesting to test whether the reactive phenotypes acquired by glia as a result of multiple exposures to HSV-1, or by recurrent reactivation of latent infections, are similar to those observed in late-onset AD.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain

Bocharova

Pandit

Molesworth

et al. 2021

Journal of Biological Chemistry

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Alzheimer’s disease (AD) is a devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is that a viral infection is key to the etiology of late-onset AD, with β-amyloid (Aβ) peptides playing a protective role. In the current study, young 5XFAD mice that overexpress mutant human amyloid precursor protein with the Swedish, Florida, and London familial AD mutations were infected with one of two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae, at three different doses. Contrary to previous work, 5XFAD genotype failed to protect mice against HSV-1 infection. The region- and cell-specific tropisms of HSV-1 were not affected by the 5XFAD genotype, indicating that host–pathogen interactions were not altered. Seven- to ten-month-old 5XFAD animals in which extracellular Aβ aggregates were abundant showed slightly better survival rate relative to their wild-type (WT) littermates, although the difference was not statistically significant. In these 5XFAD mice, HSV-1 replication centers were partially excluded from the brain areas with high densities of Aβ aggregates. Aβ aggregates were free of HSV-1 viral particles, and the limited viral invasion to areas with a high density of Aβ aggregates was attributed to phagocytic activity of reactive microglia. In the oldest mice (12–15 months old), the survival rate did not differ between 5XFAD and WT littermates. While the current study questions the antiviral role of Aβ, it neither supports nor refutes the viral etiology hypothesis of late-onset AD.

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Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain

Bocharova

Pandit

Molesworth

et al. 2021

Journal of Biological Chemistry

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“…Progressive accumulation of amyloid-β (Aβ) in form of extracellular plaques along with intracellular deposition of hyperphosphorylated tau protein in neurofibrillary tangles (NFT) are classical pathological hallmarks of Alzheimer's disease (AD) (d 'Errico & Meyer-Luehmann, 2020;Haass & Selkoe, 2007;Hyman et al, 2012;Selkoe & Hardy, 2016). Aβ deposits can also be detected intracellularly, particularly inside of neurons (Gouras et al, 2010;Gouras et al, 2012;Kumar et al, 2013;Wirths et al, 2009) and within the vasculature of the brain (Huang et al, 2021;Spangenberg et al, 2019;Thal et al, 2008;Thal et al, 2009). Aβ peptides can undergo post-translational modifications that alter aggregation and neurotoxic characteristics and might thereby modulate the pathogenesis of AD (Barykin et al, 2017;Kummer & Heneka, 2014).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction with TREM2 modulates microglial uptake of modified Aβ species

Joshi

Riffel

Satoh

et al. 2021

Glia

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Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid β peptides (Aβ). Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβ variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβ affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβ also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models.Thus, TREM2 function is important for sensing phosphorylated Aβ variants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβ species in preclinical models of Alzheimer's disease.

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“…The TAM receptor family has been reported to play a role in regulating microglial phagocytosis ( Fourgeaud et al, 2016 ; Butovsky and Weiner, 2018 ; Burstyn-Cohen and Hochberg, 2021 ; Huang et al, 2021 ). Canonical TAMR ligands such as Gas6 and Protein S bind TAM receptors through the C-terminal region and phosphatidylserine via the N-terminal region, bridging TAM expressing cells with phagocytic targets such as apoptotic bodies ( Lemke and Rothlin, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

et al. 2021

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Mouse models are vital for preclinical research on Alzheimer’s disease (AD) pathobiology. Many traditional models are driven by autosomal dominant mutations identified from early onset AD genetics whereas late onset and sporadic forms of the disease are predominant among human patients. Alongside ongoing experimental efforts to improve fidelity of mouse model representation of late onset AD, a computational framework termed Translatable Components Regression (TransComp-R) offers a complementary approach to leverage human and mouse datasets concurrently to enhance translation capabilities. We employ TransComp-R to integratively analyze transcriptomic data from human postmortem and traditional amyloid mouse model hippocampi to identify pathway-level signatures present in human patient samples yet predictive of mouse model disease status. This method allows concomitant evaluation of datasets across different species beyond observational seeking of direct commonalities between the species. Additional linear modeling focuses on decoupling disease signatures from effects of aging. Our results elucidated mouse-to-human translatable signatures associated with disease: excitatory synapses, inflammatory cytokine signaling, and complement cascade- and TYROBP-based innate immune activity; these signatures all find validation in previous literature. Additionally, we identified agonists of the Tyro3 / Axl / MerTK (TAM) receptor family as significant contributors to the cross-species innate immune signature; the mechanistic roles of the TAM receptor family in AD merit further dedicated study. We have demonstrated that TransComp-R can enhance translational understanding of relationships between AD mouse model data and human data, thus aiding generation of biological hypotheses concerning AD progression and holding promise for improved preclinical evaluation of therapies.

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Microglia use TAM receptors to detect and engulf amyloid β plaques

Cited by 252 publications

References 61 publications

Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain

Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain

Differential interaction with TREM2 modulates microglial uptake of modified Aβ species

Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

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