Biology subjects

Blumenfeld, J.

Publications and source records attributed to Blumenfeld, J..

3 recordsLinked to original sources

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↗