Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Felsky, Daniel; Roostaei, Tina; Nho, Kwangsik; Risacher, Shannon L.; Bradshaw, Elizabeth M.; Petyuk, Vlad; Schneider, Julie A.; Saykin, Andrew J.; Bennett, David A.; Jager, Philip L. De

doi:10.1101/350389

Cited by 3 publications

(2 citation statements)

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“…5A). It has been reported that an indication of microglia activation is when the cell body swells and becomes less defined and ameboid (60). The number of Iba1+ cells with changes in morphology was counted and we observed a significant increase in activated microglia in untreated Epm2b-/-(150.0 ± 9.6) compared to WT (100.0 ± 10.4, p=0.00507**,d=-1.67 large) (Fig.…”

Section: Only Propranolol Treatment Successfully Prevents Microgliosi...mentioning

confidence: 63%

Modulators of Neuroinflammation Have a Beneficial Effect in a Lafora Disease Mouse Model

2021

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Lafora disease (LD; OMIM#274780) is a fatal rare neurodegenerative disorder characterized by generalized epileptic seizures and the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), typically in the brain. LD is caused by mutations in two genes EPM2A or EPM2B, which encode respectively laforin, a glucan phosphatase, and malin, an E3ubiquitin ligase. Much remains unknown about the molecular bases of LD and, unfortunately, appropriate treatment is still missing, therefore patients die within 10 years from the onset of the disease. Recently, we have identified neuroinflammation as one of the initial determinants in LD. In this work, we have investigated anti-inflammatory treatments as potential therapies in LD. With this aim, we have performed a preclinical study in an Epm2b-/-mouse model with propranolol, a β-adrenergic antagonist, and epigallocatechin gallate (EGCG), an antioxidant from green tea extract, both of which displaying additional antiinflammatory properties. In vivo motor and cognitive behavioral tests and ex vivo histopathological brain analyses were used as parameters to assess the therapeutic potential of propranolol and EGCG. After 2 months of treatment, we observed an improvement not only in attention defects but also in neuronal disorganization, astrogliosis, and microgliosis present in the hippocampus of Epm2b-/-mice. In general, propranolol intervention was more effective than EGCG in preventing the appearance of astrocyte and microglia reactivity. In summary, our results confirm the potential therapeutic effectiveness of the modulators of inflammation as novel treatments in Lafora disease.

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Section: Only Propranolol Treatment Successfully Prevents Microgliosi...mentioning

confidence: 63%

Modulators of Neuroinflammation Have a Beneficial Effect in a Lafora Disease Mouse Model

2021

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“…TREM2, CD33, CR1), strongly suggesting a causal role in disease pathogenesis [48]. Further, polygenic modeling [65] and analyses of human cortical transcriptomes [66] converge to implicate activated microglia in the development of Tau pathology and susceptibility for AD. Numerous follow-up studies, including in mouse and cellular models, implicate microglia and astroglia with potential roles in propagating a pathogenic inflammatory cascade [67].…”

Section: Discussionmentioning

confidence: 97%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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BackgroundTau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau-versus agedependent changes. MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau WT ) or a mutation causing frontotemporal dementia (Tau R406W ). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. ResultsTau WT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. Tau R406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age-and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. BackgroundThe Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer's disease (AD) and other neurodegenerative tauopathies characterized by progressive cognitive and/or motor disability, including progressive supranuclear palsy (PSP), corticobasal degeneration, chronic traumatic encephalopathy, and certain forms of frontotemporal dementia (FTD) [1,2]. Rare mutations in the MAPT gene cause familial FTD, which is also characterized by prominent neurofibrillary tangle deposition [3][4][5]. Based on this genetic evidence, along with results from cellular and animal models [6,7], Tau is a critical mediator of age-related neurodegeneration and a causal link among this diverse group of neurologic disorders. While the precise mechanisms of Tauinduced neuronal injury remain incompletely defined, progressive synaptic dysfunction and neuronal loss likely arises from a cascade of cellular derangements, including oxidative-and immune-mediated injury, altered proteostasis, and aberrant transcription and translation [6,8].RNA-sequencing (RNA-seq) makes possible comprehensive gene expression profiling of postmortem human brain tissue in AD and o...

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Transcriptional Signatures of Progressive Neuropathology in Transgenic Models of Tau and Amyloid Pathology

et al. 2019

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Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Cited by 3 publications

References 42 publications

Modulators of Neuroinflammation Have a Beneficial Effect in a Lafora Disease Mouse Model

Modulators of Neuroinflammation Have a Beneficial Effect in a Lafora Disease Mouse Model

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Transcriptional Signatures of Progressive Neuropathology in Transgenic Models of Tau and Amyloid Pathology

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