Alzheimer & Parkinson

Spatial omics technologies enable the precise detection of proteins and RNAs at high spatial resolution. Designing spatial omics experiments requires careful consideration of "what" targets to measure and "where" to position the field of views (FOVs). Current FOV sampling strategies often involve acquiring densely sampled FOVs and stitching them together, which is time-consuming, resource-intensive, and sometimes impossible. To optimize FOV sampling strategies, we propose SOFisher, a...

Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of...

Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and...

Loss of (m)Ca^(2+) efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mitochondrial Ca^(2+) ((m)Ca^(2+)) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of (m)Ca^(2+) uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal (m)Ca^(2+) uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in...

Amyloid precursor protein (APP) gives rise to amyloid-β, a pathological factor in Alzheimer's disease. However, the physiological role of APP and its homolog amyloid precursor-like protein 2 (APLP2), which are also widely expressed outside the nervous system, is largely unknown. Here, we show that endothelial APP and APLP2 are required for postischemia angiogenesis after myocardial infarction (MI). We found that hypoxia induced the endothelial expression of α-secretases, resulting in...

Redox signaling by nitric oxide (NO) is estimated to control a large part of the global proteome via S-nitrosylation (SNO-modification). Here, we report that RNA-binding proteins (RBPs) represent the most significantly enriched class of S-nitrosylation targets, with broad coverage of spliceosomal factors. We demonstrate that NO regulates alternative splicing (AS) and that S-nitrosylation of PTBP1, a central regulator of AS, can massively shift and contextually alter gene expression while further...

Glymphatic dysfunction may contribute to abnormal protein accumulation in Alzheimer's disease (AD). This study investigates associations between an indirect proxy of glymphatic function, plasma neurodegenerative and neuroinflammatory biomarkers, and tau-PET burden across the AD continuum. Data from 407 ADNI participants were utilized. Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) is used as a noninvasive proxy of glymphatic activity. Multivariable linear regression...

Medical image analysis for Alzheimer's Disease (AD) diagnosis faces two key challenges: capturing spatial dependencies between anatomically connected brain regions and providing clinically interpretable explanations. While Convolutional Neural Networks (CNNs) excel at local feature extraction and Vision Transformers handle long-range dependencies, neither explicitly models the relational structure between brain regions-critical for understanding disease progression. We propose a hybrid CNN-GCN...

TAR DNA-binding protein 43 (TDP-43) proteinopathy has recently emerged as a pivotal, yet underrecognized, contributor to the multifaceted neuropathology of Alzheimer's disease (AD). While amyloid-β and tau have long been established as cardinal pathological hallmarks, growing evidence delineates TDP-43 as a critical participant of neurodegeneration, intricately interwoven with amyloid and tau pathologies. TDP-43 mislocalization, post-translational modifications, and aggregation potentiate...

Innate immunity mediated by myeloid cells defends against infection and injury, but when chronically activated, it drives tissue damage and neurodegeneration. Molecular imaging with positron emission tomography (PET) enables noninvasive, real-time monitoring of such processes in vivo. However, most current neuroinflammation PET tracers lack specificity for activated myeloid cells. G protein-coupled receptor 84 (GPR84) is a promising biomarker that is selectively upregulated on activated...

Parkinson disease (PD)-associated mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. Here, we show that knockout of the LRRK2-counteracting RAB phosphatase PPM1H causes a gene-dose-dependent...

Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Among the earliest regions affected is the retrosplenial cortex (RSC), where parvalbumin-expressing (PV + ) interneurons are particularly susceptible to AD-related pathology. To understand the molecular alterations within these vulnerable neurons we employed a dual-platform spatial transcriptomics approach, integrating GeoMx Digital Spatial Profiler (DSP) and Xenium...

Once tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer's disease being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting the neurotoxicity of tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in tau-related neurodegeneration (PS19 mouse model). Tau-expressing neurons undergo cell death through Z-DNA-binding...

Multimorbidity presents challenges for research and health care. We investigated how immune-proteins influence multiple diseases to identify shared mechanisms and therapeutic opportunities. Using eight large plasma proteome GWAS, we identified cis-acting variants for 151 immune-proteins and applied cis-Mendelian randomization to assess associations with 64 diseases and biomarkers. Protein-disease communities were derived using a knowledge graph integrating multiplicity-corrected associations,...

Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and...

Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.

The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe 12 phosphomimetic serine/threonine-to-aspartate mutations in tau, which we term PAD12, that...

Parkinson's disease (PD) is characterized by abnormal beta oscillations (13-30 Hz) within the basal ganglia, which contribute not only to motor symptoms but also to sleep disturbances. In this study, we developed a computational model of the basal ganglia-thalamocortical (BGTC) network that includes the pedunculopontine nucleus (PPN), to investigate the mechanism by which the abnormal oscillations disrupt sleep. The model incorporates key nuclei, neurotransmitter systems, and neural pathways to...

Differential diagnosis of neurodegenerative parkinsonian syndromes is complicated by overlapping clinical features and frequent co-pathology that challenges the interpretation of single-protein biomarkers. We evaluated a multimodal, minimally invasive biomarker strategy integrating dermal α-synuclein and 4-repeat tau seed amplification assays (SAAs) with serum neurofilament light chain. In a prospective cohort of 166 participants (Parkinson's disease, n = 40; multiple system atrophy, n = 29;...