Biology subjects

Balusu, S.

Publications and source records attributed to Balusu, S..

5 recordsLinked to original sources

bioRxiv2024

Microglia initially seed and later reshape amyloid plaques in Alzheimer's disease

We demonstrate the dual role of microglia in Alzheimers disease (AD), initially harmful, by seeding amyloid plaques, and protective in later stages by compacting amyloid plaques. Early microglial depletion using pharmacological or genetic blockage of CSF1R reduces plaque load and associated neuritic dystrophy, while human microglia transplantation restores plaque formation, confirming their seeding role. Transplanted TREM2R47H/R47Hmicroglia exacerbate plaque pathology, highlighting microglia as key initiators of the amyloid pathology cascade.

neuroscience↗

bioRxiv2022

A multi-pronged human microglia response to Alzheimer's disease Aβ pathology

Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimers disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-{beta}. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-{beta} plaques, in contrast with the response to oligomeric A{beta}. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome.

neuroscience↗

bioRxiv2022

Long noncoding RNA MEG3 activates neuronal necroptosis in Alzheimer's disease

Abstract/SummaryNeuronal cell loss is a defining feature of Alzheimers disease (AD), but it remains unclear how neurons die and how this relates to other defining characteristics of the disease1. Existing in vivo AD models only partially recapitulate the neuropathology of AD with very mild or no neuronal cell loss. Here we demonstrate that human neurons xenografted in mouse brain exposed to amyloid pathology develop sarkosyl-insoluble tau filaments, positive Gallyas silver staining, release phosphorylated tau (P-tau181) into the blood, and display considerable neuronal cell loss, providing a model for the induction of full Tau pathology by simple exposure to amyloid pathology in AD. The alterations are specific to human neurons and contrast with the mild effects exhibited in mouse neurons. A core transcriptional program in the human neurons is characterized by strong upregulation of MEG3, a neuron-specific long noncoding RNA. MEG3 is also strongly upregulated in neurons from AD patients in situ. MEG3 expression alone is sufficient to induce necroptosis in human neurons in vitro. Orally administered small molecule receptor-interacting protein (RIP) kinase -1 and -3 inhibitors rescued the neuronal cell loss in this novel AD model. Thus, xenografted human neurons are uniquely sensitive to amyloid pathology, recapitulate all the defining neuropathological features of AD, and ultimately die by necroptosis.

neuroscience↗

bioRxiv2020

Impaired adult hippocampal neurogenesis in Alzheimer's disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimers disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

neuroscience↗

bioRxiv2019

Stem cell derived human microglia transplanted in mouse brain to study genetic risk of Alzheimer's Disease

Summary paragraphGenetics highlight the central role of microglia in Alzheimers disease but at least 36% of AD-risk genes lack good mouse orthologues. Here, we show that embryonic stem cell (ESC)-derived human microglia successfully engraft the mouse brain and recapitulate transcriptionally primary human microglia derived from human surgical samples. Upon exposure to oligomeric A{beta} a wide range of AD-risk genes are expressed that are not readily studied in current mouse models for AD. This work provides a unique humanized animal model that will allow elucidating the role of genetic risk in the pathogenesis of AD.

neuroscience↗