Alzheimer & Parkinson

Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We...

ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ER^(UPR) and mito^(UPR) has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact...

Physiological brain aging is associated with cognitive impairment and neuroanatomical changes. Brain age prediction of routine clinical 2D brain MRI scans were understudied and often unsuccessful. We developed a novel brain age prediction framework for clinical 2D T1-weighted MRI scans using a deep learning-based model trained with research grade 3D MRI scans mostly from publicly available datasets (N = 8681; age = 51.76 ± 21.74). Our model showed accurate and fast brain age prediction on...

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also...

The fruit fly Drosophila melanogaster emerges as an affordable, genetically tractable model of behavior and brain diseases. However, despite the surprising level of evolutionary conservation from flies to humans, significant genetic, circuit-level, and behavioral differences hinder the interpretability of fruit fly models for human disease. Therefore, to allow a more direct fly-versus-human comparison, we surveyed the rarely exploited, rich behavioral repertoire of fruit flies with genetic...

Blood perfusion delivers oxygen and nutrients to all cells, making it a fundamental feature of brain organization. How cerebral blood perfusion maps onto micro-, meso- and macro-scale brain structure and function is therefore a key question in neuroscience. Here we analyze pseudo-continuous arterial spin labeling (ASL) data from 1305 healthy individuals in the HCP Lifespan studies (5-22 and 36-100 years) to reconstruct a high-resolution normative cerebral blood perfusion map. At the cellular and...

Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading...

This study explores the potential of adeno-associated virus serotype 9 (AAV9) to deliver therapeutic genes directly into the memory circuit throughout the olfactory bulb (OB), a critical memory and sensory processing region. Using convection-enhanced delivery (CED) of AAV9 encoding green fluorescent protein (GFP), we mapped the extensive neural connectivity from the OB to key memory-related brain regions, including the entorhinal cortex (EC) and hippocampus. Our findings reveal significant...

Deficits in the autophagy-lysosomal pathway facilitate intracellular microtubule associated protein tau (MAPT) accumulation in Alzheimer disease (AD). Aerobic exercise (AE) has been recommended as a way to delay and treat AD, but the exact effects and mechanisms have not been fully elucidated. Here, we found that AE (8-week treadmill running, 40 min/day, 5 days/week) alleviated autophagy-lysosomal defects and MAPT pathology through the activation of β2-adrenergic receptors (β2-AR) in MAPT P301L...

No abstract

Polygenic risk scores (PRSs) predict an individual's genetic risk for complex diseases, yet their utility in elucidating disease biology remains limited. We introduce scPRS, a graph neural network-based framework that computes single-cell-resolved PRSs by integrating reference single-cell chromatin accessibility profiles. scPRS outperforms traditional PRS approaches in genetic risk prediction, as demonstrated across multiple diseases including type 2 diabetes, hypertrophic cardiomyopathy,...

Alzheimer's disease (AD) is increasingly recognized as a condition shaped not only by central nervous system pathology but also by complex, bidirectional interactions between the gut, brain, and immune system. This review synthesizes emerging evidence on gut-brain-immune dysregulation in AD, with particular attention to how chronic stress, microbial imbalance, and neuroimmune signaling converge to influence disease risk and progression. We move beyond traditional microbiome-focused perspectives...

Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the...

Network hyperexcitability is one of the hallmarks of the early stage of Alzheimer's disease (AD). In this issue of Neuron, Papanikolaou¹ and coworkers show that AD-mediated alterations start at the excitatory-inhibitory subcircuit in the deep layers of the cortex.

RET is a receptor tyrosine kinase that plays important roles in development, cancers, and Parkinson's disease. Here, we identify immunoglobulin superfamily member 10 (IGSF10) as a RET antagonist. We show that Ewing sarcoma depends on IGSF10 and that IGSF10 prevents RET-mediated activation of cdc42, a Rho family G protein and a key regulator of Ewing sarcoma growth as well as cell migration. We demonstrate that IGSF10 binds RET and GAS1, a cell surface RET inhibitor, and assembles an inhibitory...

Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These...

Midnolin (Midn) was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MIDN remained largely unknown for many years after its discovery, its molecular functions and relevance to diseases have gradually become clearer. In PC12 cells, a rat neuronal model cell line, liquidity factors that are necessary for neurite outgrowth are reported to induce...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were...

Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to...

Measuring splicing and chromatin accessibility simultaneously in frozen tissues remains challenging. Here we combined single-cell isoform RNA sequencing and assay for transposase accessible chromatin (ScISOr-ATAC) to interrogate the correlation between these modalities in single cells in human and rhesus macaque frozen cortical tissue samples. Applying a previous definition of four 'cell states' in which the transcriptome and chromatin accessibility are coupled or decoupled for each gene, we...