👤 Ana-Caroline Raulin

The rare APOE3-Christchurch (APOE3Ch) variant is linked to resistance against PSEN1 p.E280A-driven autosomal dominant Alzheimer's disease (AD). Recent studies in AD mouse models have demonstrated an effect of APOE3Ch in reducing tau pathology and tau propagation, yet its effects on amyloid pathology and related toxicity are not fully understood. While prior studies have reported reduced amyloid pathology with APOE3Ch, we extended this knowledge by investigating how astrocyte-specific expression of APOE3Ch impacts amyloid pathology and related responses in 5xFAD mice, an amyloid mouse model. Using adeno-associated virus (AAV)-mediated gene delivery, we overexpressed APOE3 or APOE3Ch in astrocytes of 5xFAD mice at the neonatal stage, then analyzed their effects during the advanced stage of amyloid pathology. Astrocytic APOE expression significantly reduced amyloid burden, neuritic dystrophy, and gliosis compared to GFP controls. Notably, astrocytic APOE3Ch expression, relative to APOE3, markedly lowered oligomeric Aβ levels and promoted the formation of more compact, fibrillar plaques, suggesting a shift toward a less toxic aggregation profile. Transcriptomic profiling of cortical tissue revealed broad downregulation of immune-related and proteostatic pathways. These findings indicate that astrocytic APOE3Ch sufficiently attenuates Aβ pathology and related toxicity, supporting its potential as a therapeutic modifier for AD. Show less

Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer. Wnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were examined in patient-specific iPSC-derived neurons and cerebral organoids carrying We herein report that CI-994 is not only a potent class I HDAC inhibitor but also an activator of Wnt/β-catenin signaling. Mechanistically, activation of Wnt/β-catenin signaling by CI-994 is associated with stabilizing Wnt co-receptor LRP6 protein and modulating HDAC activity. Importantly, CI-994 significantly increases histone acetylation, activates Wnt/β-catenin signaling, and decreases tau phosphorylation in patient-specific iPSC-derived cerebral organoids carrying Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy. The online version contains supplementary material available at 10.1186/s13195-026-01982-0. Show less

Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment. Show less