👤 Takahisa Kanekiyo

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

Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial. The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD. Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase. Academic and clinical centers. All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants. Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining 'delayed start' (core:placebo followed by OLE:lecanemab) and 'early start' (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months. 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort. In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time. Clarity AD NCT03887455. Show less

Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer's disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with 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

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions. Show less