Biology subjects

Haure-Mirande, J.-V.

Publications and source records attributed to Haure-Mirande, J.-V..

7 recordsLinked to original sources

bioRxiv2025

miR155 triplicated in Down syndrome regulates hippocampal GABAergic neurogenesis in Alzheimer's disease

MicroRNA dysregulation is implicated in neurodegenerative disorders, including Alzheimers disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown. We found that MIR155HG (miR155 host gene) colocalizes with APP (amyloid-beta precursor protein) in a neuron-specific, topologically-associated domain (TAD) within a regulatory network, in the obligate portion of chromosome 21 triplicated in DS which causes AD neuropathology and in most cases, dementia. We investigated miR155 role during neuron development and then validated these findings in an amyloidopathy model. In human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs), cortical neurons and cortical organoids, MIR155 deletion enhanced NSC proliferation, ventral patterning and GABAergic interneuron generation. However, MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. MIR155 upregulates its mRNA targets, NR2F1/2, key modulators of hippocampal GABAergic interneuron development. In an amyloidopathy mouse model, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons. These findings reveal previously unrecognized miR155 roles in NSC dynamics and GABAergic interneuron development which directionally diverge from extensively studied microglial miR155 in their beneficial vs negative impact on AD mouse models, suggesting that approaching miR155 therapeutically may require balancing the effects in neurons and microglia.

neuroscience↗

bioRxiv2022

INPP5D limits plaque formation and glial reactivity in the APP/PS1 mouse model of Alzheimer's disease

The dual specificity lipid/protein phosphatase SHIP1 (encoded by the INPP5D gene) is enriched in myeloid cells. Single nucleotide polymorphisms (SNPs) in INPP5D coding and non-coding regions impact risk for developing late onset sporadic Alzheimers disease (LOAD). We present pathological analyses with spatial transcriptomics of mice with tamoxifen-sensitive microglial knockdown of Inpp5d and show exacerbated plaque pathology, plaque-associated microglial density, and altered gene expression around plaques, suggesting novel markers for plaque-associated reactive microglia.

neuroscience↗

bioRxiv2022

Orally active mGluR2/3 metabotropic antagonist pro-drug mimics the beneficial effects of physical exercise on neurogenesis, behavior, and exercise-related molecular pathways in an Alzheimer's disease mouse model

Modulation of physical activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimers disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of cerebrovascular accumulation of oligomeric A{beta}E22Q (APPE693Q = "Dutch APP") reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of the Dutch APP mice. Here we show that (i) administration of BCI-838, physical exercise, or a combination of BCI-838 and physical exercise enhanced AHN in a four-month old mouse model of AD amyloid pathology (APPKM670/671NL/ PSEN1{Delta}exon9 = APP/PS1), (ii) administration of BCI-838 alone or associated with physical exercise led to stimulation of AHN and improvement in both spatial and recognition memory, (iii) significantly, the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment up-regulated brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-MTOR pathway, and metabotropic glutamate receptors, and down-regulated EIF5A of ketamine-modulating mTOR activity, and finally (iv) qPCR findings validate a significantly strong association between increased BDNF levels and BCI-838 treatment. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHN, learning behavior, and anxiety in a mouse model of AD neuropathology.

neuroscience↗

bioRxiv2020

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice

Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimers disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgf{beta} and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-{beta} (A{beta}) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

neuroscience↗

bioRxiv2019

Further evidence of increased human Herpesvirus in Alzheimer's disease

The recent coordination of scientific and political efforts within the field of Alzheimers disease (AD) research coupled with the rapid evolution of molecular profiling technologies has enabled the generation of unprecedented repositories of biological sequence data available for investigation by the scientific community. Next-generation sequences (NGS) represent complex readouts of cellular transcriptomic and genomic states, and hold the potential to illuminate disease biology via unexpected applications of collected data. We recently reported a multiomic study of the Alzheimers associated brain virome, leveraging NGS data to understand the potential relevance of viral activity to AD. We observed increased abundance of human herpesvirus 6A (HHV-6A), HHV-7, and herpes simplex virus 1 (HSV-1) genomes in banked postmortem brains from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. Although these findings might be of general interest to the field, such analyses present novel methodological challenges that have not been well characterized. The viral abundances that we detected were generally quite low, and, in many samples, no virome was detected. We sought to understand whether such sparsity might be associated with the spurious detection of differential abundance. Herein, we employ a simulation approach, which indicates that sparsity in abundance actually biases against the detection of significant differences between AD and control subjects. We also report new results based on previously unpublished whole genome sequences that show increases in both abundance and prevalence of HHV-6A in AD, consistent with our previously reported results. These findings, as well as reports from many other groups employing a variety of approaches, support the dedication of a coordinated effort toward a comprehensive characterization of the microbiome of the brain affected by AD. Such studies should advance our understanding of the potential clinical relevance of these observations.

neuroscience↗

bioRxiv2019

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Human brain transcriptomes can highlight biological pathways associated with Alzheimers disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 AD-associated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age- and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntingtons disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

systems biology↗

bioRxiv2018

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimers disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.\n\nOne sentence summaryVGF protects against Alzheimers disease

genomics↗