Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease

Crapser, Joshua; Ochaba, Joseph; Soni, Neelakshi; Reidling, Jack C.; Thompson, Leslie M.; Green, Kim N.

doi:10.1093/brain/awz363

Cited by 112 publications

(136 citation statements)

References 138 publications

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“…MMP9) or other ECM-degrading proteases that act on PNN components [33] . However, PNN loss is also reported in other neurological disorders such as seizure [34] and prion disease [35] , and recent work from our lab identified a role for microglia-mediated PNN loss in Huntington's disease [36] . Although PNNs are reported to protect neurons against tau [ 37 , 38 ] and Aβ pathology [39] , the extent to which PNN loss occurs in human and animal models of AD – where microglia are inextricably linked to disease pathogenesis – remains controversial [40] , [41] , [42] , [43] .…”

Section: Introductionmentioning

confidence: 76%

“…To measure the total WFA+ material associated with microglia, the WFA+ intensity sum of each IBA1+ spot was added together for each sample. CSPG immunoreactivity was measured as integrated signal density in ImageJ (NIH) as before [36] . For the analysis of human tissue, the number of ACAN+ (aggrecan clone 7D4) PNNs and Thio-S+ dense-core plaques were manually quantified and averaged across 4 regionally distinct 20X Z-stack max projections of cortical gray matter per brain sample for n = 9 non-demented control and n = 12 AD brains to determine statistical differences.…”

Section: Methodsmentioning

confidence: 99%

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Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

et al. 2020

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Background Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial. Methods Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia. Findings Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence. Interpretation We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain. Funding The NIH (NIA, NINDS) and the Alzheimer's Association.

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Section: Introductionmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

et al. 2020

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“…Furthermore, microglial dysfunction in the hippocampus results in reduction of dendritic spines along with increased ECM expression (Bolós et al, 2018), suggesting microglia participate in degrading the ECM to allow for increased synaptic plasticity. A recent study demonstrated that pharmacological depletion of microglia prevented PNN decreases that normally occur in a mouse model of Huntington's disease and improved memory function (Crapser et al, 2020), suggesting that microglia play a critical role in regulating PNN composition. Taken together, the current evidence suggests that cathepsin-S from microglia is an optimal candidate for contributing to modification of PNN composition to allow dynamic regulation of synaptic plasticity during sleep.…”

Section: Introductionmentioning

confidence: 99%

Circadian Rhythms of Perineuronal Net Composition

Pantazopoulos

Gisabella

Rexrode

et al. 2020

eNeuro

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Perineuronal nets (PNNs) are extracellular matrix (ECM) structures that envelop neurons and regulate synaptic functions. Long thought to be stable structures, PNNs have been recently shown to respond dynamically during learning, potentially regulating the formation of new synapses. We postulated that PNNs vary during sleep, a period of active synaptic modification. Notably, PNN components are cleaved by matrix proteases such as the protease cathepsin-S. This protease is diurnally expressed in the mouse cortex, coinciding with dendritic spine density rhythms. Thus, cathepsin-S may contribute to PNN remodeling during sleep, mediating synaptic reorganization. These studies were designed to test the hypothesis that PNN numbers vary in a diurnal manner in the rodent and human brain, as well as in a circadian manner in the rodent brain, and that these rhythms are disrupted by sleep deprivation. In mice, we observed diurnal and circadian rhythms of PNNs labeled with the lectin Wisteria floribunda agglutinin (WFA1 PNNs) in several brain regions involved in emotional memory processing. Sleep deprivation prevented the daytime decrease of WFA1 PNNs and enhances fear memory extinction. Diurnal rhythms of cathepsin-S expression in microglia were observed in the same brain regions, opposite to PNN rhythms. Finally, incubation of mouse sections with cathepsin-S eliminated PNN labeling. In humans, WFA1 PNNs showed a diurnal rhythm in the amygdala and thalamic reticular nucleus (TRN). Our results demonstrate that PNNs vary in a circadian manner and this is disrupted by sleep deprivation. We suggest that rhythmic modification of PNNs may contribute to memory consolidation during sleep.

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“…If delivery of a drug is restricted to the CNS, any impact on immune system cells in the periphery will be minimal. However, CNS-targeted HTT-lowering could affect microglia in ways both plausibly beneficial in terms of dampening the hyper-reactive inflammatory phenotype of the cells when they express the disease mutation 70 , or less so if loss of the protective effects of wtHTT in microglia means they are less able to deal with the stresses associated with the disease, other insults and/or aging. Any such negative effect, however, might well be outweighed by the overall diminishing of an environment stressful to microglia by the reduced presence of mHTT and its toxic effects.…”

Section: Discussionmentioning

confidence: 99%

Wild-type huntingtin regulates human macrophage function

O’Regan

Farag

Ostroff

et al. 2020

Sci Rep

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The huntingtin (HTT) protein in its mutant form is the cause of the inherited neurodegenerative disorder, Huntington’s disease. Beyond its effects in the central nervous system, disease-associated mutant HTT causes aberrant phenotypes in myeloid-lineage innate immune system cells, namely monocytes and macrophages. Whether the wild-type form of the protein, however, has a role in normal human macrophage function has not been determined. Here, the effects of lowering the expression of wild-type (wt)HTT on the function of primary monocyte-derived macrophages from healthy, non-disease human subjects were examined. This demonstrated a previously undescribed role for wtHTT in maintaining normal macrophage health and function. Lowered wtHTT expression was associated, for instance, with a diminished release of induced cytokines, elevated phagocytosis and increased vulnerability to cellular stress. These may well occur by mechanisms different to that associated with the mutant form of the protein, given an absence of any effect on the intracellular signalling pathway predominantly associated with macrophage dysfunction in Huntington’s disease.

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Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease

Cited by 112 publications

References 138 publications

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

Circadian Rhythms of Perineuronal Net Composition

Wild-type huntingtin regulates human macrophage function

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