Biology subjects

Grone, B.

Publications and source records attributed to Grone, B..

5 recordsLinked to original sources

bioRxiv2025

Tri-AD: Hippocampal cell-type-specific responses to age, sex and APOE genotype

Alzheimers disease (AD) risk is strongly shaped by age, sex, and the apolipoprotein E {varepsilon}4 (APOE4) allele--the strongest genetic risk factor for late-onset AD. While each factor has been studied independently, their combined impact on cellular and molecular processes remains unclear. Here, we used single-nucleus RNA sequencing (snRNA-seq) to profile hippocampal cell states in a sex-balanced cohort of human APOE4/4 and APOE3/3 knock-in mice across 6, 12, and 18 months of age. We identify sex as the major driver of variation in cell-type abundance and find that oligodendrocytes exhibit pronounced male-biased transcriptional sensitivity to APOE4. Differential expression and cell-cell communication analyses further reveal sex-divergent temporal trajectories in inhibitory neurons, with females showing early APOE4-associated suppression of synaptic pathways and males displaying a delayed but convergent decline. Together, these findings clarify how age, sex, and APOE genotype jointly regulate cell-type-specific gene expression and intercellular communication in the aging hippocampus, providing an innovative and publicly accessible database for aging and AD research and related precision medicine.

bioinformatics↗

bioRxiv2023

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimers Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of A{beta} and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis. HIGHLIGHTSO_LITransplanted human APOE4 neurons generate A{beta} and p-tau aggregates in APOE4-KI mouse hippocampus. C_LIO_LIHuman neuronal APOE4 promotes the formation of dense-core A{beta} plaques and p-tau aggregates. C_LIO_LIMicroglia is required for human neuronal APOE4-driven formation of p-tau aggregates. C_LIO_LIscRNA-seq reveals enrichment of MHC-II microglia in mice with human APOE4 neuron transplants. C_LI

neuroscience↗

bioRxiv2023

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimers disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

neuroscience↗

bioRxiv2022

Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer's disease

Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimers disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.

neuroscience↗

bioRxiv2021

Phenotypic analysis of catastrophic childhood epilepsy genes: The Epilepsy Zebrafish Project

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. A unifying epilepsy classification scheme was developed based on local field potential recordings and blinded scoring from ~3300 larvae. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

neuroscience↗