Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R
            <sup>+/−</sup>
            mouse model of ALSP, which can be rescued via CSF1R inhibitors

Arreola, Miguel A.; Soni, Neelakshi; Crapser, Joshua; Hohsfield, Lindsay A.; Elmore, Monica R. P.; Matheos, Dina P.; Wood, Marcelo A.; Swarup, Vivek; Mortazavi, A; Green, Kim N.

doi:10.1126/sciadv.abg1601

Cited by 40 publications

(61 citation statements)

References 91 publications

(160 reference statements)

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“…A study, in which adult CSF1R± mice were treated with persistent low-grade PLX5622 at different stages of the disease, has found that modulating microglial phenotypes could reverse presynaptic and ECM alterations induced by CSF1R haploinsufficiency and improved cognition without altering neuronal populations. This finding suggests that microglia are viable targets for therapeutic intervention early in the disease ( Arreola et al, 2021 ).…”

Section: Based On the Proliferation Of Resident Microgliamentioning

confidence: 99%

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Wang

et al. 2021

Front. Aging Neurosci.

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Colony-stimulating factor-1 receptor-microglial encephalopathy is a rare rapidly progressive dementia resulting from colony-stimulating factor-1 receptor (CSF1R) mutations, also named pigmentary orthochromatic leukodystrophy (POLD), hereditary diffuse leukoencephalopathy with spheroids (HDLS), adult-onset leukoencephalopathy with axonal spheroids, and pigmented glia (ALSP) and CSF1R-related leukoencephalopathy. CSF1R is primarily expressed in microglia and mutations normally directly lead to changes in microglial number and function. Many animal models have been constructed to explore pathogenic mechanisms and potential therapeutic strategies, including zebrafish, mice, and rat models which are with CSF1R monogenic mutation, biallelic or tri-allelic deletion, or CSF1R-null. Although there is no cure for patients with CSF1R-microglial encephalopathy, microglial replacement therapy has become a topical research area. This review summarizes CSF1R-related pathogenetic mutation sites and mechanisms, especially the feasibility of the microglia-original immunotherapy.

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Section: Based On the Proliferation Of Resident Microgliamentioning

confidence: 99%

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Wang

et al. 2021

Front. Aging Neurosci.

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“…Homozygous CSF1R mutations in the human brain lead to almost complete absence of microglia ( Oosterhof et al, 2019 ). Using an inducible Cx3cr1 CreERT2/+ ; Csf1r fl/+ system to conditional delete one Csf1r allele also affects microglial homeostasis ( Arreola et al, 2021 ). CSF1R is highly conserved among vertebrates, including zebrafish, which possess two paralogous genes: csf1ra and csf1rb .…”

Section: Physiological Role Of Csf1r In the Central Nervous Systemmentioning

confidence: 99%

“…Hence, potential effects of CSF1R or CSF1R-mediated microglia depletion on DNs formation may also play important role in neuropathology of ALSP and AD. CSF1R inhibitor PLX5622 prevented the loss of presynaptic surrogates and the extracellular matrix (ECM) structure perineuronal nets in Csf1r +/– mice ( Arreola et al, 2021 ). An induced pluripotent stem cell line from a patient with ALSP has been generated, which may allow the investigation of CSF1R mutations in a human cell model and shed new light on the therapeutic strategies of this intractable ALSP ( Hayer et al, 2018b ).…”

Section: Csf1r In Neurodegenerative Diseasesmentioning

confidence: 99%

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Duan

Wang

et al. 2021

Front. Aging Neurosci.

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The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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“…The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.483490 doi: bioRxiv preprint synaptic and neuronal loss (Arreola et al, 2021;Elmore et al, 2018;Hong et al, 2016;Rice et al, 2015;Schafer et al, 2012;Spangenberg et al, 2016;Wang et al, 2020;Werneburg et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…During AD, microglia mount an inflammatory response to Aβ plaques, as evidenced by findings in both human AD brains and animal models of the disease (Leng and Edison, 2021; Sayed et al, 2021). Accumulating evidence implicates microglia in several AD- related processes including plaque formation and growth (Spangenberg et al, 2019), plaque compaction (Casali et al, 2020; Spangenberg et al, 2019), constituting a protective barrier against dystrophic neurites (Condello et al, 2015), promoting or preventing development and spreading of Tau pathology (Shi et al, 2019), cerebral amyloid angiopathy (Spangenberg et al, 2019), destruction of perineuronal nets (Arreola et al, 2021; Crapser et al, 2020), as well as synaptic and neuronal loss (Arreola et al, 2021; Elmore et al, 2018; Hong et al, 2016; Rice et al, 2015; Schafer et al, 2012; Spangenberg et al, 2016; Wang et al, 2020; Werneburg et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Tran¹,

Kawauchi

Rezaie³

et al. 2022

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Genome-Wide Association Studies revealed the TREM2 R47H variant as one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current TREM2*R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. We have developed the Trem2R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele, without evidence of cryptic splicing products, and appropriate inflammatory responses to cuprizone challenge. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in response to pathology. At an early disease stage (4 mo), homozygous Trem2R47H NSS; hemizygous 5xFAD (Trem2R47H NSS ; 5xFAD) mice have reduced size and number of microglia plus impaired interaction with plaques, that is associated with increased dystrophic neurites and axonal damage detected through plasma neurofilament light chain (NfL) level and suppressed inflammation. However, homozygosity for Trem2R47H NSS suppressed LTP deficits and presynaptic puncta loss caused by the 5xFAD transgene array. At a more advanced disease stage (12 mo,) Trem2R47H NSS ; 5xFAD mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Furthermore, (age) Trem2R47H NSS ; 5xFAD mice also display robust LTP deficits and exacerbated presynaptic loss. Collectively, we provide a Trem2R47H variant mouse without cryptic splicing, and demonstrate it has disease stage dependent effects when combined with a plaque bearing model, with an initial loss of function that ultimately resolves, giving rise to a unique interferon signature and associated tissue damage.

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Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R ^+/− mouse model of ALSP, which can be rescued via CSF1R inhibitors

Cited by 40 publications

References 91 publications

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

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Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R +/− mouse model of ALSP, which can be rescued via CSF1R inhibitors

Cited by 40 publications

References 91 publications

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Contact Info

Product

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Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R ^+/− mouse model of ALSP, which can be rescued via CSF1R inhibitors