Thakore, R. | bioRxiv Science

bioRxiv2026

Neuronal age drives β-sheet accumulation and, together with ApoE4, enhances synaptic Aβ localization in APPNL-F neurons

Amyloid-{beta} (A{beta}) accumulation and aggregation are defining features of Alzheimers disease (AD), but the earliest cellular events driving these processes remain poorly understood. Here, we investigate A{beta} dynamics in primary neurons derived from APPNL-F knock-in mice, which express human APP and A{beta} at endogenous (non-overexpressed) levels. Using correlative optical photothermal infrared (OPTIR) spectromicroscopy and immunofluorescence, we show that physiological APPNL-F expression is sufficient to drive intraneuronal A{beta} accumulation at synapses. Modelling neuronal aging through prolonged culture reveals a marked increase in synaptic A{beta} burden accompanied by {beta}-sheet-rich structural transitions Supplementation with astrocyte-derived apolipoprotein E (ApoE) isoforms demonstrates that ApoE4 markedly increases synaptic A{beta} accumulation while reducing {beta}-sheet content relative to untreated cultures, suggesting a potential shift toward less fibrillar species. Together, these findings establish APPNL-F neurons as a physiologically relevant system for dissecting early A{beta} pathology and show that both A{beta} quantity (accumulation) and quality (structural maturation) are regulated by aging and ApoE genotype. This work provides mechanistic insight into the earliest molecular events that may underlie synaptic vulnerability in AD.

neuroscience↗

bioRxiv2017

Drosophila Kruppel homolog 1 represses lipolysis through interaction with dFOXO

Transcriptional coordination is a vital process contributing to metabolic homeostasis. As one of the key nodes in the metabolic network, the forkhead transcription factor FOXO has been shown to interact with diverse transcription co-factors and integrate signals from multiple pathways to control metabolism, oxidative stress response, and cell cycle. Recently, insulin/FOXO signaling has been implicated in the regulation of insect development via the interaction with insect hormones, such as ecdysone and juvenile hormone. In this study, we identified an interaction between dFOXO and the zinc finger transcription factor Kruppel homolog 1 (Kr-h1), one of the key players in juvenile hormone signaling in Drosophila. We found that Kr-h1 mutants have reduced triglyceride storage, decreased insulin signaling and delayed larval development. Notably, Kr-h1 physically and genetically interacts with dFOXO in vitro and in vivo to regulate the transcriptional activation of adipose lipase brummer (bmm). The transcriptional co-regulation by Kr-h1 and dFOXO may represent a broad mechanism by which Kruppel-like factors integrate with insulin signaling to maintain metabolic homeostasis and coordinate organism growth.

genetics↗