Alzheimer & Parkinson

Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several...

Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss,...

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, yet the cellular mechanisms linking APOE variants to disease risk remain unclear. We previously found that APOE4 expression causes lipid droplet accumulation in oligodendrocytes, reducing myelination, but the underlying mechanisms were unknown. Using a genome-wide CRISPR screen and assay for transposase-accessible chromatin (ATAC) sequencing in human-induced pluripotent stem cell (iPSC)-derived oligodendrocytes, we...

Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined. Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states. Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient...

Single-cell resolution spatial transcriptomics provides a great opportunity to explore the complex cellular contents in different tissues. Here we introduce SpatialZoomer, a spectral graph-based method that applies a set of low-pass filters to efficiently extract spatial molecular features from spatial transcriptomics data at multiple resolutions or scales, including the single cell scale, the niche scale with dozens of closely interacting cells and the domain scale with spatially organized cell...

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Pleiotrophin (PTN) is a heparin-binding growth factor that plays a pivotal role in neurodevelopment, neuroplasticity, and neuroinflammation. PTN signals through a multi-receptor network involving protein tyrosine phosphatase receptor type ζ (PTPRZ1), syndecans (particularly syndecan-3), integrins, nucleolin, and neuropilin-1. Anaplastic lymphoma kinase (ALK) has also been functionally linked to PTN signaling, although whether PTN directly binds and activates it remains debated. This review...

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial...

Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with...

Alzheimer's disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow ( < 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulation in the early stages...

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Obesity and diabetes are well-established risk factors for Alzheimer's disease (AD), implicating metabolic dysfunction in AD pathogenesis. Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five-week-old female 3xTg-AD mice were preconditioned...

Targeting microglia with adeno-associated viruses (AAVs) remains challenging because of inefficient transduction, off-target expression, and inconsistent payload performance. Here, we develop an integrated, Cre-independent AAV platform that combines a compact 446-bp microglia-specific regulatory element (MSRE), a high-yield AAV2/9.m capsid, microRNA-mediated neuronal de-targeting, and a microglia-tailored codon-optimization strategy. Following direct intracranial delivery, the optimized vector...

With the global aging population, age-related neurodegenerative diseases and cerebrovascular diseases have become major public health challenges. As a modifiable lifestyle strategy, dietary intervention shows significant potential in delaying brain aging and reducing the risk of neurodegenerative and cerebrovascular diseases. Caloric restriction (CR) and dietary restriction (DR), two important nutritional intervention approaches, exhibit substantial neuroprotective potential through multiple...

Chromatin structure is essential for gene regulation and genome stability, as neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we perform Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice and compare them to the previously published Hi-C data...

Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with...

DNA methylation (DNAm) plays a critical role in Alzheimer's disease (AD). Previous epigenome-wide association studies using 450K arrays captured limited CpG coverage and often focused on a single neuropathological measure. Here we profiled DNAm in 1,250 postmortem prefrontal cortex samples from the Rush Alzheimer's Disease cohorts using the Infinium MethylationEPIC v2 array (~930,000 CpGs) and performed epigenome-wide association studies of multiple neuropathologic measures, including AD...

Alzheimer's disease (AD) disproportionately affects women, yet mechanisms underlying this sex difference remain unclear. Histone variants are overrepresented components of aging neuronal chromatin, but their contribution to AD is unknown. Here, we identify the histone variant H2A.Z as a sex-specific regulator of AD in the postmortem human hippocampus and in 5xFAD mice. H2A.Z occupancy decreased in female but increased in male AD patients. In females, reduced H2A.Z occupancy at the transcription...

Alzheimer's disease (AD) is the most common cause of dementia and remains without a cure; recently introduced disease-modifying therapies provide only modest slowing in selected patients. Physical exercise is associated with better cognitive and functional outcomes, but the molecular mechanisms underlying these benefits remain incompletely understood. DNA methylation is a potential interface linking environmental stimuli to gene regulation and neural function. This narrative review examines...

Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous...