Dysregulation of Phosphoinositide 5-Phosphatases and Phosphoinositides in Alzheimer's Disease

Ando, Kunie; Erneux, Christophé; Homa, Mégane; Houben, Sarah; Fisenne, Marie-Ange De; Brion, Jean Pierre; Leroy, Karelle

doi:10.3389/fnins.2021.614855

Cited by 14 publications

(14 citation statements)

References 41 publications

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“…7,9 INPP5D encodes for the SH2-domaincontaining inositol phosphatase SHIP-1 and its expression in the brain is almost exclusively restricted to microglia. 10,11 Outside of the brain, SHIP-1 is abundantly expressed by most hematopoietically derived innate and adaptive immune cells where it functions to dampen immune responses, such as proinflammatory cytokine production, phagocytosis, and reactive oxygen species generation. [12][13][14][15] Moreover, SHIP-1 has also been reported to affect the proliferation and survival of circulating myeloid cells.…”

Section: Introductionmentioning

confidence: 99%

“…One recently identified gene locus that has been strongly linked to LOAD risk is INPP5D 7,9 . INPP5D encodes for the SH2‐domain‐containing inositol phosphatase SHIP‐1 and its expression in the brain is almost exclusively restricted to microglia 10,11 . Outside of the brain, SHIP‐1 is abundantly expressed by most hematopoietically derived innate and adaptive immune cells where it functions to dampen immune responses, such as proinflammatory cytokine production, phagocytosis, and reactive oxygen species generation 12–15 .…”

Section: Introductionmentioning

confidence: 99%

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The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology

Samuels

Moore

Ennerfelt

et al. 2023

Alzheimer's & Dementia

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IntroductionMutations in INPP5D, which encodes for the SH2‐domain‐containing inositol phosphatase SHIP‐1, have recently been linked to an increased risk of developing late‐onset Alzheimer's disease. While INPP5D expression is almost exclusively restricted to microglia in the brain, little is known regarding how SHIP‐1 affects neurobiology or neurodegenerative disease pathogenesis.MethodsWe generated and investigated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to ascertain the function of microglial SHIP‐1 signaling in response to amyloid beta (Aβ)‐mediated pathology.ResultsSHIP‐1 deletion in microglia led to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP‐1 loss enhanced microglial plaque containment and Aβ engulfment when compared to microglia from Cre‐negative 5xFAD Inpp5dfl/fl littermate controls.DiscussionThese results define SHIP‐1 as a pivotal regulator of microglial responses during Aβ‐driven neurological disease and suggest that targeting SHIP‐1 may offer a promising strategy to treat Alzheimer's disease.Highlights Inpp5d deficiency in microglia increases plaque‐associated microglia numbers. Loss of Inpp5d induces activation and phagocytosis transcriptional pathways. Plaque encapsulation and engulfment by microglia are enhanced with Inpp5d deletion. Genetic ablation of Inpp5d protects against plaque‐induced neuronal dystrophy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology

Samuels

Moore

Ennerfelt

et al. 2023

Alzheimer's & Dementia

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“…PICALM and other endocytic proteins encoded by AD susceptibility genes may be implicated in such steps that lead to dysfunction and breakdown of finely tuned cellular physiological functions. PICALM may be a small piece of complex endocytic machinery that may be vulnerable to neurodegeneration [ 169 ].…”

Section: Discussionmentioning

confidence: 99%

PICALM and Alzheimer’s Disease: An Update and Perspectives

Ando

Nagaraj

Küçükali

et al. 2022

Cells

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Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as the most significant genetic susceptibility locus after APOE and BIN1. PICALM is a clathrin-adaptor protein that plays a critical role in clathrin-mediated endocytosis and autophagy. Since the effects of genetic variants of PICALM as AD-susceptibility loci have been confirmed by independent genetic studies in several distinct cohorts, there has been a number of in vitro and in vivo studies attempting to elucidate the underlying mechanism by which PICALM modulates AD risk. While differential modulation of APP processing and Aβ transcytosis by PICALM has been reported, significant effects of PICALM modulation of tau pathology progression have also been evidenced in Alzheimer’s disease models. In this review, we summarize the current knowledge about PICALM, its physiological functions, genetic variants, post-translational modifications and relevance to AD pathogenesis.

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“…Microglia are specialized tissue-resident macrophages in the brain, which are centrally involved in neuroinflammatory and neurodegenerative diseases [75]. Dysregulated PI3K signaling in microglia has been linked to chronic neuroinflammation, a characteristic of Alzheimer's disease (AD) and other neurodegenerative conditions [76,77]. In mouse models of AD, SHIP1 expression increases predominantly in plaque-associated microglia, where it is positively associated with disease progression [78,79].…”

Section: Microgliamentioning

confidence: 99%

SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy

Yeoh,

Krebs

2023

Eur J Immunol

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Phosphoinositide‐3‐kinase/AKT (PI3K/AKT) signaling plays key roles for the regulation of cellular activity in both health and disease. In immune cells, this PI3K/AKT pathway is critically regulated by the phosphoinositide phosphatase SHIP1, which has been reported to modulate the function of most immune subsets. In this review, we summarize our current knowledge of SHIP1 with a focus on innate immune cells, where we reflect on the most pertinent aspects described in the current literature. We also present the several small molecule agonists and antagonists of SHIP1 developed the last two decades, which have led to improved outcomes in several pre‐clinical models of disease. We outline these promising findings and put them in relation with human diseases with unmet medical needs, where we discuss the most attractive targets for immune therapies based on SHIP1 modulation.This article is protected by copyright. All rights reserved

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Dysregulation of Phosphoinositide 5-Phosphatases and Phosphoinositides in Alzheimer's Disease

Cited by 14 publications

References 41 publications

The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology

The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology

PICALM and Alzheimer’s Disease: An Update and Perspectives

SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy

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