Alzheimer & Parkinson

Cellular deconvolution estimates cell-type fractions from bulk transcriptomic data, but current methods often overlook cell type-specific expression varying across samples, discrepancies between bulk and single-cell data, or lack guidance on reference data selection and integration. Therefore, we present BLEND, a hierarchical Bayesian method that leverages multiple single-cell reference datasets to perform cellular deconvolution. BLEND estimates cellular fractions accurately by learning the most...

Intercellular nanotubular networks mediate material exchange, but their existence in neurons remains to be explored in detail. We identified long, thin dendritic filopodia forming direct dendrite-dendrite nanotubes (DNTs) in mammalian cortex. Super-resolution microscopy in dissociated neurons revealed DNTs' actin-rich composition and dynamics, enabling long-range calcium ion (Ca^(2+)) propagation. Imaging and machine learning-based analysis validated in situ DNTs as anatomically distinct from...

Integrating single-cell RNA sequencing with Genome-Wide Association Studies (GWAS) can uncover cell types involved in complex traits and disease. However, current methods often lack scalability, interpretability, and robustness. We present seismic, a framework that computes a novel specificity score capturing both expression magnitude and consistency across cell types and introduces influential gene analysis, an approach to identify genes driving each cell type-trait association. Across over...

The accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer's disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose...

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On the basis of extensive mechanistic research over three decades, Parkinson disease (PD) and related synucleinopathies have been proposed to be combined proteinopathies and lipidopathies. Evidence strongly supports a physiological and pathogenic interplay between the disease-associated protein α-synuclein and lipids, with a demonstrable role for lipids in modulating PD phenotypes in the brain. Here, we refine this hypothesis by proposing PD to be a disease specifically involving metabolic...

Parkinson's disease (PD) is a neurodegenerative condition characterized by the presence of intraneuronal aggregates containing fibrillar ɑ-synuclein known as Lewy bodies. These large end-stage species are formed by smaller soluble protein nanoscale assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. Until now, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualize nanoscale assemblies in human brain...

Extracellular Tau determines the progression of Alzheimer's disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their...

Meningeal lymphatic vessels (MLVs) have been identified to associate with various neurological diseases, such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and brain tumors. Damage to MLVs can exacerbate the pathological progression of these diseases and significantly impede therapeutic efficacy. Therefore, targeted repair of the damaged MLVs has emerged as an innovative strategy for treating these central nervous system (CNS) diseases. In...

The conversion of proteins into insoluble fibrillar aggregates known as amyloid occurs in a wide variety of diseases, e.g., Alzheimer's disease, amyotrophic lateral sclerosis, systemic transthyretin amyloidosis, and multisystem atrophy. There are more than 60 disease-associated amyloid-forming proteins, and amyloid formation can occur sporadically or can be induced or accelerated by genetic mutations. This Review discusses structural mechanisms by which genetic changes promote amyloid formation...

Multi-organ research investigates interconnections among multiple human organ systems, enhancing our understanding of human aging and disease mechanisms. Here we use multi-organ imaging, individual- and summary-level genetics, and proteomics data consolidated via the MULTI Consortium to delineate a brain-heart-eye axis using brain patterns of structural covariance (PSCs), heart imaging-derived phenotypes (IDPs) and eye IDPs. We find that proteome-wide associations of the PSCs and IDPs show...

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major...

Excessive endoplasmic reticulum (ER) stress and neuronal apoptosis contribute to neurodegeneration in Parkinson's disease (PD). However, the molecular mechanisms underlying these perturbations and how they are directly regulated remain unclear. B cell receptor-associated protein 31 (BAP31), which is highly expressed in the ER, has been shown to participate mainly in regulating ER stress and apoptosis. Here, our results showed that BAP31 expression was dramatically decreased in PD. Notably,...

Glycine transporter type 1 (GlyT1) regulates extracellular glycine levels and modulates N-methyl-D-aspartate receptor (NMDAR) activity, positioning it as a promising target in excitotoxic and ischemic conditions. While previous studies have shown that GlyT1 inhibition prior to injury confers neuroprotection, its therapeutic potential in a post-ischemic context remains unclear. Here, we investigated the neuroprotective effects of NFPS, a selective GlyT1 inhibitor, administered after the induction...

There is increasing evidence that the pathogenesis of Parkinson's disease (PD) is closely related to mitochondrial dysfunction and iron deposition. Activin A (Act A) is a homodimeric cytokine from the TGF-β superfamily and has neuroprotective effects in various neurological diseases. However, the specific mechanisms by which Act A exerts a neuronal protective effect in PD remain unclear. In this study, we selected lipopolysaccharide (LPS) -induced PD model mice to investigate the mechanism of...

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with mitochondrial dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. The silent information regulator 2 (Sir2) family of proteins, known as sirtuins (SIRT1 - SIRT7), is nicotinamide adenine dinucleotide (NAD^(+))-dependent histone deacetylases that regulate important signal transduction pathways in both prokaryotes and eukaryotes. An increasing number of studies revealed that...

Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer's disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well...

The molecular mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, remain poorly understood. Proteomics offers a crucial approach to elucidating AD pathogenesis, as alterations in protein expression are more directly linked to phenotypic outcomes than changes at the genetic or transcriptomic level. In this study, we develop multiscale proteomic network models for AD by integrating large-scale matched proteomic and genetic data from brain regions...

Preclinical evidence suggests positive symptomatic and neuroprotective effects of hypoxic conditioning in Parkinson's disease (PD). This study (NCT05214287) investigated the safety, feasibility, short-term symptomatic and downstream effects of hypoxic conditioning in individuals with PD. 20 individuals with PD (mean age 62, 10 women, Hoehn-Yahr 1.5-3) completed randomized controlled double-blinded multiple N-of-1 trials. Each participant underwent five different 45-minute hypoxia interventions...

GBA is the major risk gene for Parkinson's disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities....