Alzheimer & Parkinson

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....

Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing...

Microtubules are dynamic cytoskeletal polymers whose lattice architecture regulates force generation, nucleotide hydrolysis, and recognition by motor proteins and microtubule-associated proteins (MAPs). Microtubule-stabilizing agents (MSAs), including taxanes and laulimalide/peloruside-site ligands, suppress depolymerization by binding to defined lattice sites, yet stabilization is not structurally neutral. How ligand chemistry reshapes lattice organization and function remains unresolved. Here,...

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Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were...

Quantitative insights into brain metabolism are essential for advancing our understanding of the energy dynamics in the brain. Here, we present a nanowatt-resolution biocalorimeter capable of real-time metabolic heat output measurements of individual, live Drosophila melanogaster brains. Using this platform, we show that female brains, across multiple genotypes, exhibit a significantly higher metabolic rate (∼10%-15%) than male brains at a young age (<10 days old) and follow distinct metabolic...

Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that has been related to abnormal functional connectivity across motor, cognitive, and limbic networks. However, it remains unclear how directional (i.e., effective) connectivity between various networks is altered by an actual FOG-related motor imagery task. Twenty-four individuals with PD (11 freezers and 13 non-freezers) and 15 healthy controls underwent functional MRI. Participants performed a motor imagery task...

Parkinson's disease leads to a spectrum of locomotor deficits that vary in severity with the nature of daily activities and the fluctuating physiology of patients. Many of these deficits remain inadequately addressed by existing deep brain stimulation therapies that rely on activity-agnostic parameters optimized for cardinal motor symptoms. By contrast, therapies embedding activity-specific parameters have the potential to better address the entire range of symptoms. Here we expose physiological...

A randomized crossover study of five patients with Parkinson's disease (PD) demonstrates that gait-synchronized adaptive deep brain stimulation is feasible and safe, and reduces falls compared with continuous stimulation. Gait dysfunction in PD is a major source of disability and is often insufficiently treated by continuous deep brain stimulation (cDBS). Although adaptive DBS (aDBS) has shown efficacy for other motor symptoms using β-based, state-driven neural signals, gait is a dynamic,...

Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more...

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