Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

Highlights d In vivo chimeric Alzheimer's disease modeling of apoE4 toxicity d Excitatory and inhibitory neurons have distinct transcriptional responses to apoE4 d Human iPSC (hiPSC)-derived neurons generate Ab aggregates in vivo d Mouse apoE4 microglia are deficient in clearing Ab aggregates made by human neurons

Molecular damage of DNA plays an important role in the cell killing and several anti-neoplastic agents exert their cytotoxic effects by inducing DNA damage in the cancer cells. DNA damaging effect of various concentrations of berberine chloride (BCL), an isoquinoline alkaloid was studied in HeLa cells by alkaline comet assay. The DNA damage has been expressed as olive tail moment (OTM). Incubation of HeLa cells with BCL for 4 h showed greater amount of DNA damage (OTM) than 2 h treatment. BCL treatment caused a concentration dependent rise in the DNA damage in HeLa cells and exposure of HeLa cells with 1 µg/ml BCL caused a10 fold rise in baseline DNA damage, whereasa maximum rise in DNA damage was observed in HeLa cells exposed to 8 µg/ml BCL. The study of DNA repair kinetics at different BCL post-treatment times revealed a constant rise in the DNA damage in BCL treated cells up to 24 h except for 1 -4 µg/ml BCL, where the highest DNA damage was observed at 12 h post-BCL treatment. The clonogenic assay showed that BCL treatment resulted in a concentration dependent rise in its cell killing effect. The cell survival and molecular DNA damage in HeLa cells treated with BCL has an inverse correlation indicating that with increased DNA damage cell survival declined. Our study demonstrates that anti-neoplastic effect of BCL is mainly due to its ability to cause damage to the cellular genome.

Highlights d Local field potential signatures of entorhinal cortex (EC) and CA3 coupling to CA1 d Suppressing DG and CA3 PV + or SST + neurons increases CA3 output to CA1 d Suppressing PV + neurons increases CA3-CA1 coupling and decreases EC-CA1 coupling d Suppressing SST + neurons decreases CA3-CA1 coupling and increases EC-CA1 coupling