BIN1 favors the spreading of Tau via extracellular vesicles

Crotti, Andrea; Sait, Hameetha Rajamohamend; McAvoy, Kathleen M.; Estrada, Karol; Ergün, Ayla; Szak, Suzanne; Marsh, Graham; Jandreski, Luke; Peterson, Michael A.; Reynolds, Taylor L.; Dalkilic-Liddle, Isin; Cameron, Andrew; Cahir-McFarland, Ellen; Ransohoff, Richard M.

doi:10.1038/s41598-019-45676-0

Cited by 128 publications

(126 citation statements)

References 73 publications

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“…APOE [53], BIN1 [11], PICALM [3], CLU [66] and PTK2B [15]). Our present study on PICALM supports the hypothesis that one of the common key cascades of LOAD may be the modulation of tau pathology and taumediated neurodegeneration, as observed in the experimental models for APOE and BIN1 [13,51].…”

Section: Direct Association Between Tau and The Proteins Coded By Thesupporting

confidence: 87%

Picalm reduction exacerbates tau pathology in a murine tauopathy model

et al. 2020

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Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubuleassociated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/− by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/− mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPicalm+/− had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and taumediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

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Section: Direct Association Between Tau and The Proteins Coded By Thesupporting

confidence: 87%

Picalm reduction exacerbates tau pathology in a murine tauopathy model

et al. 2020

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“…BIN1 was found to be the second most predominant loci involved in AD progression (following APOE) [88] and was not involved in later steps of amyloidogenic processing from later stage AD progression, falling in line with previously identified involved steps [89]. In addition, BIN1 has been found to link to microglia [25] and be commonly implicated in Tauopathy, further supporting the status of BIN1 as a high risk loci for AD [90]. Similarly, CLU has been shown to be enriched and heavily implicated in multigene pathways, particularly APOE, to lead to eventual AD progression.…”

Section: Gene Regulatory Network Associated With Functional Interplasupporting

confidence: 74%

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

Jin

Rehani

Ying

et al. 2020

Preprint

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Strong phenotype-genotype associations have been reported across brain diseases. However, understanding underlying gene regulatory mechanisms remains challenging, especially at the cellular level. To address this, we integrated the multi-omics data at the cellular resolution of the human brain: cell-type chromatin interactions, epigenomics and single cell transcriptomics, and predicted cell-type gene regulatory networks linking transcription factors, distal regulatory elements and target genes (e.g., excitatory and inhibitory neurons, microglia, oligodendrocyte). Using these cell-type networks and disease risk variants, we further identified the cell-type disease genes and regulatory networks for schizophrenia and Alzheimer's disease. The celltype regulatory elements (e.g., enhancers) in the networks were also found to be potential pleiotropic regulatory loci for a variety of diseases. Further enrichment analyses including gene ontology and KEGG pathways revealed potential novel cross-disease and disease-specific molecular functions, advancing knowledge on the interplays among genetic, transcriptional and epigenetic risks at the cellular resolution between neurodegenerative and neuropsychiatric diseases. Finally, we summarized our computational analyses as a general-purpose pipeline for predicting gene regulatory networks via multi-omics data.Recent analyses have also revealed that brain disease risk variants are located in non-coding regulatory elements (e.g., enhancers) and that the risk genes likely have cell-type specific effects including neuronal and non-neuronal types [25,26]. In addition, recent single-cell studies 68 TFs,

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“…Interestingly, the composition of EVs strictly reflects the type and the activation state of donor cells, evoking, in the case of microglia, a detrimental or a beneficial response depending on the parental inflammatory or pro-resolving phenotype [ 65 , 66 ]. Due to these features, microglial EVs have been identified as mediators of inflammation and neurodegeneration, playing a pivotal role in spreading pathological misfolded protein aggregates [ 67 , 68 , 69 , 70 ] and in triggering harmful responses in recipient neurons and glial cells [ 71 , 72 ]. On the other hand, they have been also described as vehicles of pro-regenerative molecules, promoting remyelination and brain repair [ 69 , 72 , 73 ].…”

Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Raffaele

Lombardi

Verderio

et al. 2020

Cells

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Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.

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BIN1 favors the spreading of Tau via extracellular vesicles

Cited by 128 publications

References 73 publications

Picalm reduction exacerbates tau pathology in a murine tauopathy model

Picalm reduction exacerbates tau pathology in a murine tauopathy model

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

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