Alzheimer & Parkinson

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are key mediators of calcium ion (Ca^(2+)) influx required for proper neuronal function. Excessive NMDAR-mediated Ca^(2+) influx is neurotoxic and associated with neurological disease. Memantine and ketamine, two NMDAR antagonists with overlapping binding sites in the NMDAR channel, are of high clinical interest. Whereas memantine is a well-tolerated Alzheimer's disease medication, ketamine is a fast-acting antidepressant with abuse potential and...

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein. The development of a positron emission tomography tracer to detect aggregates of misfolded α-synuclein could revolutionize early diagnosis, disease monitoring, and the evaluation of therapeutic efficacy. Here, we present the development, preclinical validation, and first-in-human evaluation of [^(11)C]MODAG-005. In vitro binding...

Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain's white matter (WM) microstructure. Here we present a large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N = 54,583...

Selective butyrylcholinesterase (BChE) inhibition is gaining renewed attention as a potential therapeutic strategy for Alzheimer's disease (AD), particularly in advanced stages marked by a shift from acetylcholinesterase (AChE) to BChE dominance. Beyond cholinergic regulation, BChE participates in metabolic, inflammatory, and affective pathways, including the enzymatic control of acyl ghrelin that influences appetite, energy balance, and mood. Preclinical and experimental evidence suggests that...

Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating...

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported...

Endoplasmic reticulum autophagy (ER-phagy) is a selective autophagy pathway in which receptor proteins target ER membranes and proteins for degradation, yet its role in Alzheimer's disease (AD) remains unclear. Here, we identify FAM134B/RETREG1 as a specific ER-phagy receptor mediating amyloid precursor protein (APP) degradation. FAM134B directly interacts with ER-localized wild-type and familial mutant APP via their C-terminal domains and recruits LC3 through its LC3-interacting region (LIR) to...

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and...

Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation,...

Nearly two-thirds of Americans with Alzheimer's disease (AD) are women. Prior research suggested that women with AD have lower brain estrogen levels than those without AD. However, how estrogen deficiency modulates this sex-based difference in AD vulnerability is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, including the hippocampus. This study aims to assess the mechanistic link between brain-selective...

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...