Variant TREM2 Signaling in Alzheimer's Disease

Olufunmilayo, Edward O.; Holsinger, R. M. Damian

doi:10.1016/j.jmb.2022.167470

Cited by 20 publications

(11 citation statements)

References 73 publications

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“…Dup/Dup patients showed nearly three times higher TREM2 levels than the Wt/Wt. Since TREM2 signaling is involved in microglial activation, metabolic fitness and Aβ plaque protection 28,29 , the increase in TREM2 levels in Dup patients is consistent with the observed increase in the number of IBA1 positive cells per plaque.…”

Section: Discussionsupporting

confidence: 71%

An intragenic duplication withinSIRPβ1shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response

García‐Alberca

Rojas

Sánchez-Mejías

et al. 2022

Preprint

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Microglia play an important role in the maintenance of brain homeostasis, and microglial dysfunction plays a causative role in Alzheimer disease pathogenesis. Here we focus on the signal regulatory protein SIRPβ1, a surface receptor expressed on the myeloid cells that triggers amyloidβ and cell debris phagocytosis via TYROBP. We found that a common intragenic duplication alters the SIRPβ1 protein isoform landscape affecting both extracellular and transmembrane domains, which compromise their ability to bind oligomeric Aβ and their affinity for TYROBP. Epidemiological studies show that patients with mild cognitive impairment that are homozygous for the SIRPβ1 duplication allele show an increased cerebrospinal fluid tTau Aβ ratio (p-value=0.018) and a higher risk to develop AD (OR=1.678, p-value=0.018). Magnetic resonance imaging at diagnosis showed that AD patients with the duplication allele exhibited a worse initial response to the disease. At the moment of diagnosis all patients showed equivalent Mini-Mental State Examination scores. However AD patients with the duplication allele had less hippocampal degeneration (Beta= -0.62, p-value = 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline after correcting by baseline (p-value = 0.013). Transcriptional analysis of the patients hippocampus also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Given the recent pharmacological approaches focused on the TREM2-TYROBP axis, we consider that the presence of this structural variant might be considered as a potential modulator of this causative pathway.

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Section: Discussionsupporting

confidence: 71%

An intragenic duplication withinSIRPβ1shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response

García‐Alberca

Rojas

Sánchez-Mejías

et al. 2022

Preprint

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“…Activation of TREM2 modulates several microglial functions including inflammatory cytokine release, phagocytosis, proliferation, survival and differentiation (Deczkowska et al, 2020 ; Konishi & Kiyama, 2020 ). The main mechanism of TREM2 activation and signaling is via ligand binding to the extracellular domain, resulting in binding of TREM2 to DAP‐12, whose cytosolic ITAM (immunoreceptor tyrosine‐based activation motif) domains activate SYK tyrosine kinase, although TREM2 can also signal via binding DAP‐10 rather than DAP‐12 (Olufunmilayo & Holsinger, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…TREM2 expression has been shown to be upregulated in microglia that associate with amyloid plaques in Alzheimer's disease (AD) (Brendel et al, 2017 ; Giraldo et al, 2013 ; Jay et al, 2015 ; Yuan et al, 2016 ). Genome wide association studies (GWAS) have identified several rare, heterozygous variants of TREM2 that increase risk of AD, including R47H TREM2, which increases AD risk about four‐fold (Giraldo et al, 2013 ; Guerreiro et al, 2012 ; Jonsson et al, 2013 ; Olufunmilayo & Holsinger, 2022 ). Understanding how this single mutation confers this considerably increased risk of AD when present on only one allele, may give important insights into the mechanism of AD and how to prevent it.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's disease‐associated R47H TREM2 increases, but wild‐type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss

Popescu

Butler

Allendorf

et al. 2022

Glia

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Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems.Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F.

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“…AD places a tremendous socioeconomic burden on caregivers and on the healthcare system as a whole. Despite ~115 years of intense and directed research, no effective treatment or cure for AD exists, although many insights into the molecular-genetic nature of this age-related disease have been established (Alzheimer et al, 1995 ; Kaur et al, 2015 ; Lane et al, 2018 ; Dong et al, 2021 ; Hermans et al, 2021 ; Trejo-Lopez et al, 2021 ; Liu et al, 2022 ; Olufunmilayo and Holsinger, 2022 ; Pogue et al, 2022 ; Rastegar-Moghaddam et al, 2022 ; Singh et al, 2022 ; Tahami Monfared et al, 2022 ; Yoon et al, 2022 ). As a devastating, inflammatory, and terminal neurodegenerative disorder, one molecular genetic component that has emerged at the forefront of current AD research is the DNA-binding element NF-kB, probably the single most important transcription factor yet identified in the complex neuropathology of AD.…”

Section: Alzheimer's Disease (Ad): Epidemiology and Basic Featuresmentioning

confidence: 99%

NF-kB (p50/p65)-Mediated Pro-Inflammatory microRNA (miRNA) Signaling in Alzheimer's Disease (AD)

Lukiw

2022

Front. Mol. Neurosci.

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Variant TREM2 Signaling in Alzheimer's Disease

Cited by 20 publications

References 73 publications

An intragenic duplication withinSIRPβ1shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response

An intragenic duplication withinSIRPβ1shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response

Alzheimer's disease‐associated R47H TREM2 increases, but wild‐type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss

NF-kB (p50/p65)-Mediated Pro-Inflammatory microRNA (miRNA) Signaling in Alzheimer's Disease (AD)

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