Biology subjects

Blumenfeld, J.

Publications and source records attributed to Blumenfeld, J..

7 recordsLinked to original sources

bioRxiv2025

Neuronal APOE4 reduction with an APOE-I3-targeting ASO protects against neurodegeneration and neuroinflammation in an Alzheimer's disease mouse model

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease (AD). Within the central nervous system (CNS), APOE is produced by a variety of cell types, with differential roles in AD pathogenesis. Studies have shown that APOE4 produced by neurons plays a central role in promoting the development of major AD pathologies, including p-tau accumulation, neuroinflammation, and neurodegeneration, highlighting its role as an upstream initiating factor that affects other cell types and downstream AD-related pathologies. Here, we demonstrate that antisense oligonucleotides (ASOs) targeting APOE-I3, a neuron-specific splicing variant of APOE mRNA, effectively reduce APOE expression in neurons in vitro and in vivo. Treating PS19 tauopathy mice expressing APOE4 with this APOE-I3-targeting ASO reduces neuronal APOE4, rescues neurodegeneration, and diminishes neuroinflammation. Strikingly, the extent of neuronal APOE4 reduction predicts the efficacy of rescuing neurodegeneration. Single nucleus RNA-sequencing demonstrated that APOE-I3-targeting ASO treatment decreases disease associated neuronal and glial subtypes and increases a disease-protective microglial subtype. These findings suggest that preferential knockdown of neuronal APOE4 with an APOE-I3-targeting ASO protects against key hallmarks of AD pathology, elucidating a potential therapeutic approach for treating APOE4-driven AD.

neuroscience↗

bioRxiv2025

Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease

Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimers disease (AD). With APOE4 broadly expressed in the brain, its cell-type-specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient for lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes, all promoting lipid pathology. Primary mouse co-culture experiments showed that neuronal APOE4 drives microglial lipid accumulation via contact-dependent mechanisms involving uptake of lipids from neurons and oligodendrocytes. These findings establish neuronal APOE4 as a key driver of lipid accumulation via neuron-oligodendrocyte-microglia interactions, providing mechanistic insight into APOE4-driven lipid pathology in AD.

neuroscience↗

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↗

bioRxiv2025

Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model

Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimers disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation--the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.

neuroscience↗

bioRxiv2024

Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease

Alzheimers disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model, this combination therapy significantly improved memory function and reduced AD-related pathologies compared to vehicle and single-drug treatments. Single-nuclei transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/627436v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e67fd5org.highwire.dtl.DTLVardef@1d2b779org.highwire.dtl.DTLVardef@10b6efforg.highwire.dtl.DTLVardef@1a44394_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

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↗