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The authors conducted a genome-wide association study of bipolar disorder (BD) in Han Chinese and integrated PGC4 East Asian and European datasets, discovering 23 novel loci, prioritizing 39 credible risk genes and implicating BD-related cell types and druggable targets.
In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.
Examining human brain organoids and ex vivo neonatal murine cortical slices demonstrates that structured neuronal sequences emerge independently of sensory input, highlighting the potential of brain organoids as a model for neuronal circuit assembly.
Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.
The authors developed a mouse brain atlas using local dendritic morphological patterns from 101,136 neurons. This representation not only improves anatomical precision but also uncovers associations between local dendritic architecture and long-range neuronal projections.
Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.
Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.
Astrocytes are associated with Alzheimer’s disease pathogenesis. We found that the transcription factor Sox9 functions to enhance astrocytic phagocytosis of Aβ plaques via MEGF10, and this clearance of plaques is associated with the preservation of cognitive function in mouse models.
Early tactile deficits in patients with Alzheimer disease (AD) and AD mouse models map to tau pathology in spinal cholecystokinin (CCK) neurons. In AD mice, reducing tau or c-Maf levels in spinal CCK neurons restores touch and benefits cognition, suggesting that these deficits are a noninvasive peripheral indication of early AD and offer a tractable target for intervention.
The dopamine motivating animals to perform a current behavior also desensitizes local D2 dopamine receptors. Dopamine signaling is less effective in subsequent rounds, resulting in repetition-induced devaluation of behavior.
This study reveals how Tau pathology in spinal neurons contributes to early tactile deficits in Alzheimer’s disease, linking sensory dysfunction to cognitive decline. It highlights potential peripheral biomarkers and new therapeutic targets beyond the brain.
This Perspective discusses the challenges involved in translating optogenetic research into clinical practice, including clinical and pragmatic choices, potential toxicity and immune responses, regulatory issues and ethical considerations.
Confidence is key to decision-making, but the dynamics of confidence formation remain elusive. We show that neural populations in parietal cortex reflect the parallel processes of forming a decision and confidence in the decision.
Using a large dataset of neural recordings and modern video-analysis methods, Wang, Kurgyis et al. describe a rich, structured encoding of movement across and within brain areas in mice performing both instructed and uninstructed movements in a task.
Single-cell ATAC/RNA multiomic profiling was used to investigate how oligodendrocyte lineage cells respond across multiple disease stages within a mouse MS model, revealing early activation of immune genes along with oligodendrocyte subtype-specific responses.
In this issue of Nature Neuroscience, Golden et al. unveil a mouse model that enables in vivo ‘switching’ from the Alzheimer’s risk gene APOE4 to the protective gene APOE2. This genetic conversion reshapes Alzheimer’s disease-related metabolism, reduces neuropathology, and enhances cognition, demonstrating the beneficial effects of APOE genetic targeting as a promising therapeutic strategy.
