Biology subjects

Wolfs, L.

Publications and source records attributed to Wolfs, L..

9 recordsLinked to original sources

bioRxiv2025

The Alzheimer's therapeutic Lecanemab induces an amyloid-clearing program in microglia

Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-A{beta} antibody, mediates amyloid clearance by triggering effector functions in the microglia. Using a human microglia xenograft model, we show that Lecanemab significantly reduces A{beta} pathology and associated neuritic damage, while neither Fc-inactivated Lecanemab nor microglia deficiency elicit this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon gamma genes, and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting A{beta} clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through Fc fragment, providing critical insights for optimizing anti-amyloid therapies in AD.

neuroscience↗

bioRxiv2024

The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease

Microglia play a key role in the response to amyloid beta in Alzheimers disease (AD). In this context, a major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent on APOE genotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoforms protective role.

genomics↗

bioRxiv2023

The MIR-NAT MAPT-AS1 does not regulate Tau expression in human neurons

The MAPT gene encodes Tau protein, a member of the large family of microtubule-associated proteins. Tau forms large insoluble aggregates that are toxic to neurons in several neurological disorders and neurofibrillary Tau tangles represent a key pathological hallmark of Alzheimers disease (AD) and other tauopathies1,2. Several Tau-lowering strategies are being investigated as a potential treatment for AD but the mechanisms that regulate Tau expression at the transcriptional or translational level are not well understood3,4. Recently, Simone et al.5 reported the discovery of a new type of natural antisense transcripts called MIR-NATs (referring to Mammalian-wide Interspersed Repeats - Natural Antisense Transcripts). Simone and colleagues used MAPT-AS1, a MIR-NAT associated to the MAPT gene as an archetype of this new class of long non-coding RNAs. According to Simone et al., MAPT-AS1 represses Tau translation by competing for ribosomal RNA. We investigated the potential functions of MAPT-AS1 in neurons using the same gain- and loss-of-function experiments as described in the original report and expanded our analysis with complementary approaches. Our data do not support a role for MAPT-AS1 in regulating Tau expression in human neurons and urge to cautiously interpret the data provided by Simone et al.5.

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

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's Disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimers disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex, several years before amyloid deposition. We found the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astroglial calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral hyperactivity. In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

neuroscience↗

bioRxiv2020

Single nucleus sequencing fails to detect microglial activation

Single nucleus RNA-Seq (snRNA-Seq) methods are used as an alternative to single cell RNA-Seq methods, as they allow transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-Seq is able to detect cellular state in human tissue. Indeed, snRNA-Seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimers Disease. A comparison of microglia from single cells and single nuclei of four human subjects reveals that ~1% of genes is depleted in nuclei compared to whole cells. This small population contains 18% of genes previously implicated in microglial activation, including APOE, CST3, FTL, SPP1, and CD74. We confirm our findings across multiple previous single nucleus and single cell studies. Given the low sensitivity of snRNA-Seq to this population of activation genes, we conclude that snRNA-Seq is not suited to detecting cellular activation in microglia in human disease.

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

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

The linear cause-consequence relationship linking amyloid-{beta} peptide (A{beta}) accumulation to neuronal dysfunction in Alzheimer disease (AD) is gradually replaced by the concept that A{beta} initiates complex inflammatory-like cellular alterations that progressively become A{beta} independent and lead to brain dyshomeostasis. Little is known about the pathophysiology of this cellular phase of AD. We use here two orthogonal technologies, Spatial Transcriptomics and in situ sequencing, to analyse the transcriptome changes in cells in the amyloid-{beta} plaque niche in a knock-in mouse model for AD. We identify a multicellular co-expressed gene network of 57 Plaque-Induced Genes (PIGs) that define a series of co-ordinated and spatially restricted microglia, astroglia and oligodendrocyte responses to progressing amyloid plaques encompassing complement, oxidative stress and inflammation. A separate oligodendrocyte network suggests abnormal myelination. Spatial Transcriptomics provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.

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↗