Alzheimer & Parkinson

Studying the genetic basis of human phenotypes involves two primary strategies. Model-system experiments generate interpretable gene networks but do not establish relevance to human disease. In contrast, statistical genetics identifies variant- and gene-level associations but cannot test mechanistic models. Here, we bridge these approaches by introducing NERINE, a hierarchical model-based rare variant association test that incorporates gene network topology while remaining robust to network...

Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes,...

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Poly-ADP-ribosylation (PARylation), catalyzed by the enzyme PARP1, involves the addition of poly-ADP-ribose polymers (PAR) and has been associated with α-synuclein aggregation in Parkinson's disease (PD) models. This study aimed to unravel the role of PARylation in α-synuclein aggregation and neuronal cell death in the complex environment of post-mortem human PD brains. Using high-resolution imaging and 3D reconstruction analysis, we observed that PAR accumulate in the cytoplasm in regions...

Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or...

Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca^(2+) levels and impaired long-term...

APOE4, the major genetic risk factor for Alzheimer's disease (AD), and ATP-binding cassette-A1 (ABCA1), required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled in coregulator TR-FRET (CRT) assays analyzing ligand-induced coactivator...

Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau, synaptic dysfunction, and chronic neuroinflammation. AD pathogenesis involves multiple central nervous system (CNS) cell types-including neurons, astrocytes, microglia, and oligodendrocytes, and, less prominently, neural stem cells (NSCs), ependymal cells, and endothelial cells-which undergo coordinated but...

Mild Behavioral Impairment (MBI) and amnestic Mild Cognitive Impairment (aMCI) are complementary early markers of Alzheimer's disease (AD), yet their combined neuroanatomical correlates and predictive value for conversion remain underexplored. In this study of 72 community-dwelling older adults (49 aMCI, 23 healthy controls), we retrospectively classified aMCI participants into non-converters (aMCI-NC, n = 31) and converters (aMCI-C, n = 18) based on longitudinal follow-up. Baseline structural...

Mitogen-activated protein kinase (MAPK) signaling is increasingly recognized as a central regulator in the pathogenesis of Parkinson's disease (PD). PD is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), driven by a complex interplay of mitochondrial dysfunction, oxidative stress, and neuroinflammation. While basal MAPK activity is essential for neuroprotection and neuronal growth, its overactivation,...

Alzheimer's disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis reveals reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in...

Dysregulation of RNA m⁶A modification has been implicated in Alzheimer's disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m⁶A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-β (Aβ) deposition. Under physiological conditions, cytosolic m⁶A-modified mt-Nd4 is recognized and degraded by the m⁶A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I-MAVS innate...

Beyond their role in energy production, mitochondria also interact with other organelles through forming membrane contacts that serve as central hubs of cellular metabolism and signaling. Aberrant mitochondria-organelle communication has been implicated in various neurodegenerative diseases, but the underlying mechanisms and their pathological consequences remain poorly understood. Here, we reveal that tauopathy synapses exhibit excessive tethering of autophagosome/autophagic vacuole...

Genome-edited human pluripotent stem cells (hPSCs) provide a powerful platform to study complex diseases such as Parkinson's disease (PD). Here, we describe iSCORE-PD, an isogenic collection of 65 genome-edited hPSC lines carrying disease-causing or high-risk variants in 11 PD-linked genes (SNCA, PRKN, PINK1, DJ1/PARK7, LRRK2, ATP13A2, FBXO7, DNAJC6, SYNJ1, VPS13C, and GBA1). All lines are derived from a well-characterized female hESC line and subjected to extensive quality control. Whole-genome...

G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that...

We report the highly enantioselective nucleophilic addition reaction of simple ketone-derived hydrazones. Accordingly, a ErCl₃-catalyzed cyanation of both aliphatic and aryl ketone hydrazones is achieved for the facile access of C^(α)-tetrasubstituted α-hydrazino nitriles in up to 96% ee, by using the sterically confined pyridinebisoxazoline (PYBOX) ligand featuring a sulfonyl group at the pyridine C4 position. This method enables the shortest catalytic enantioselective total synthesis of...

The etiology of Alzheimer's disease (AD) remains unclear but is likely driven by gene-environment interactions. We present a multi-organ untargeted metabolomics atlas (n = 2,271) paired with metagenomics data (n = 666) from two AD transgenic mouse models (3xTg and 5xFAD) under colonized and germ-free conditions. Systems-level analyses revealed clusters of dysregulated molecules across tissues, including carnitines, bile acids, B vitamins, neurotransmitters, and N-acyl lipids. Metabolic shifts...

Integrating diverse biomedical modalities is essential for robust healthcare insights, and graph-based models are increasingly used to capture complex relational structures. Yet, their clinical translation hinges on interpretability. This review surveys interpretable graph-based models applied to multimodal biomedical data, highlighting dominant trends in disease classification, static graph construction, and post-hoc explainability. We categorize explainable artificial intelligence (XAI)...

The eye is a recognized source of biomarkers for cardiovascular and neurodegenerative disease risk. Here we characterize the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic and genomic information. We trained retinal adversarial autoencoders to represent optical coherence tomography images and color fundus photographs as 256-dimensional embeddings....