Treatment of a genetic brain disease by CNS-wide microglia replacement

Shibuya, Yohei; Kumar, Kevin K.; Mader, Marius Marc-Daniel; Yoo, Yongjin; Ayala, L Angel; Zhou, Mu; Mohr, Manuel; Neumayer, Gernot; Kumar, Ishan; Yamamoto, Ryō; Marcoux, P.; Liou, Benjamin; Bennett, F. Chris; Nakauchi, Hiromitsu; Sun, Ying; Chen, Xiaoke; Heppner, Frank L.; Wyss‐Coray, Tony; Südhof, Thomas C.; Wernig, Marius

doi:10.1126/scitranslmed.abl9945

Cited by 51 publications

(63 citation statements)

References 74 publications

(97 reference statements)

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“…Alternatively, replacing older microglia with young functional phenotypes that express sufficient levels of autophagic receptors may be a promising candidate for novel cell transplantation therapy for AD. This type of microglia replacement approach has recently been attempted in a different model of ND using cutting-edge tools that incorporate bone marrow and microglia-depleting chemicals [229].…”

Section: Microglia Response To Amyloid-βmentioning

confidence: 99%

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Wendimu

Hooks

2022

Cells

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Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

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Section: Microglia Response To Amyloid-βmentioning

confidence: 99%

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Wendimu

Hooks

2022

Cells

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“…Restoring Gba function in microglia alone showed limited effect on NK cell infiltration; however, treatment with GCS inhibitor not only offset GluCer/GlcSph buildup, but also exhibited a novel immunomodulatory effect by abrogating NK cell activation. Therefore, combination therapy with GCS inhibitors and microglia-targeted therapeutics ( Shibuya et al, 2022 ) merits further exploration. In general, the immune response of NK cells is fine-tuned by a balance of stimulatory and inhibitory signals based on a distinct receptor repertoire.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy

Boddupalli

Nair

Belinsky

et al. 2022

eLife

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Background:Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features; however, the role of GBA in individual cell types and involvement of microglia, blood-derived macrophages, and immune infiltrates in nGD pathophysiology remains enigmatic.Methods:Here, using single-cell resolution of mouse nGD brains, lipidomics, and newly generated biomarkers, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons.Results:Targeted rescue of Gba in microglia and neurons, respectively, in Gba-deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced serum neurofilament light chain (Nf-L), and improved survival. Serum GlcSph concentration was correlated with serum Nf-L and ApoE in nGD mouse models as well as in GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, which was further enhanced upon treatment with brain-permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis, and reversal of neuroinflammation involving activation of microglia, brain macrophages, and NK cells.Conclusions:Together, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation. Brain-permeant small-molecule inhibitor of glucosylceramide synthase reduced the accumulation of bioactive glycosphingolipids, concomitant with amelioration of neuroinflammation involving microglia, NK cells, astrocytes, and neurons. Our findings advance nGD disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials, and illuminate therapeutic targets.Funding:Research grant from Sanofi; other support includes R01NS110354, Yale Liver Center P30DK034989, pilot project grant.

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“…Interestingly, cingulate-PSAP-deficient mice presented normal locomotion, a non-depressive state, and an intact working memory, but suffered from increased anxiety, and, more importantly, impaired sensorimotor gating. However, PSAP and PGRN are also expressed in glial cells, especially microglia [ 34 , 35 ]. Considering their trafficking between cells, the behavioral influence of neuronal PSAP removal could be affected by glial-cell-originated PSAP.…”

Section: Discussionmentioning

confidence: 99%

Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

Zhang

Flais

et al. 2022

IJMS

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Prosaposin (PSAP) and progranulin (PGRN) are two lysosomal proteins that interact and modulate the metabolism of lipids, particularly sphingolipids. Alterations in sphingolipid metabolism have been found in schizophrenia. Genetic associations of PSAP and PGRN with schizophrenia have been reported. To further clarify the role of PSAP and PGRN in schizophrenia, we examined PSAP and PGRN levels in postmortem cingulate cortex tissue from healthy controls along with patients who had suffered from schizophrenia, bipolar disorder, or major depressive disorder. We found that PSAP and PGRN levels are reduced specifically in schizophrenia patients. To understand the role of PSAP in the cingulate cortex, we used an AAV strategy to knock down PSAP in neurons located in this region. Neuronal PSAP knockdown led to the downregulation of neuronal PGRN levels and behavioral abnormalities. Cingulate-PSAP-deficient mice exhibited increased anxiety-like behavior and impaired prepulse inhibition, as well as intact locomotion, working memory, and a depression-like state. The behavioral changes were accompanied by increased early growth response protein 1 (EGR-1) and activity-dependent cytoskeleton-associated protein (ARC) levels in the sensorimotor cortex and hippocampus, regions implicated in circuitry dysfunction in schizophrenia. In conclusion, PSAP and PGRN downregulation in the cingulate cortex is associated with schizophrenia pathophysiology.

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Treatment of a genetic brain disease by CNS-wide microglia replacement

Cited by 51 publications

References 74 publications

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy

Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

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