Alzheimer's disease pathology in Nasu-Hakola disease brains

Satoh, Jun‐ichi; Kino, Yoshihiro; Yanaizu, Motoaki; Saito, Yuko

doi:10.5582/irdr.2017.01088

Cited by 22 publications

(16 citation statements)

References 21 publications

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“…Rare but lethal, NHD is caused by a loss of function of TREM2 or its signaling partner DAP12 (51). Significant demyelination is found in patient brains (199) and in mouse models (200, 201), however signs of Aβ and tau pathology are limited, despite the role of TREM2 in AD (202). Overactive microglial phagocytosis is also a driver of the pathology found in FTD; loss of expression of functional progranulin results in increased C1q production and complement-mediated synapse loss during aging (203).…”

Section: Phagocytosis In Disease Statesmentioning

confidence: 99%

Phagocytosis in the Brain: Homeostasis and Disease

et al. 2019

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Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.

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Section: Phagocytosis In Disease Statesmentioning

confidence: 99%

Phagocytosis in the Brain: Homeostasis and Disease

et al. 2019

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“…Neuropsychological and functional nuclear imaging ( 99m Tc-ECD SPECT) tests in heterozygotes in a family carrying this same mutation showed deficits of visuospatial memory associated with hypoperfusion in the basal ganglia implying an overlap of pathogenic mechanisms between AD and PLOSL 75 . However, immunohistochemistry analyses of five brains of patients with PLOSL revealed no amyloid plaques or amyloid angiopathy, and only a small number of tau-tangle bearing neurons, mostly in the hippocampus, suggesting that TREM2 loss of function does not accelerate AD pathology 76 . Additionally, analyses of TYROBP genetic variability have also not shown associations with cognitive impairment in a Finnish cohort 77 or as the cause of dementia in Turkish patients 78 .…”

Section: Trem2 Mutations Cause Ploslmentioning

confidence: 90%

The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

Carmona

Zahs

et al. 2018

The Lancet Neurology

191

144

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Alzheimer's disease is a genetically complex disorder; rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been shown to as much as triple an individual's risk of developing Alzheimer's disease. TREM2 is a transmembrane receptor expressed in cells of the myeloid lineage, and its association with Alzheimer's disease supports the involvement of immune and inflammatory pathways in the cause of the disease, rather than as a consequence of the disease. TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques. TREM2 variants have also been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and frontotemporal dementia. Although the low frequency of TREM2 variants makes it difficult to establish robust genotype-phenotype correlations, such studies are essential to enable a comprehensive understanding of the role of TREM2 in different neurological diseases, with the ultimate goal of developing novel therapeutic approaches.

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“…Therefore, TREM2 deficiency manifests more strongly in humans than in mice, suggesting that mice evolved more efficient mechanisms to tolerate loss of TREM2 in physiological settings or that TREM2 signaling becomes more important at ages that mice never reach. The latter seems more plausible because NHD patients only develop symptoms at an age of 20-30 years (Satoh et al, 2018), and TREM2-deficent mice produce a range of phenotypes in diverse pathologies, chronic and acute, suggesting a role in controlling myeloid phenotypes in response to tissue damage, which steadily accumulates with aging.…”

Section: Physiological Roles Of Trem2mentioning

confidence: 99%

“…The ITAM motif of DAP12 is phosphorylated by SRC tyrosine kinase upon activation of colony-stimulating factor 1 receptor (CSF1R); therefore, the activity of this signaling will also modulate TREM2-dependent activation (Otero et al, 2009;Zou et al, 2008). Interestingly, humans with a genetic background causing only partial CSF1R activity show a set of symptoms similar to Nasu-Hakola disease patients (Klü nemann et al, 2005;Satoh et al, 2018), carrying TREM2-inactivating mutations, suggesting synergy between the two pathways (Hume et al, 2020). TREM2-and CSF1R-dependent activation of DAP12 is also key for induction of the b-catenin pathway in differentiating mouse osteoclasts (Otero et al, 2009(Otero et al, , 2012.…”

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confidence: 99%

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Deczkowska

Weiner

Amit

2020

Cell

337

315

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Alzheimer's disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.

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Alzheimer's disease pathology in Nasu-Hakola disease brains

Cited by 22 publications

References 21 publications

Phagocytosis in the Brain: Homeostasis and Disease

Phagocytosis in the Brain: Homeostasis and Disease

The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

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