Alzheimer & Parkinson

Pilat, Le, and colleagues¹ reveal that the Alzheimer's-linked TREM2 T96K variant, previously labeled gain of function based on in vitro assays, unexpectedly weakens microglial activation and disease-associated microglial responses in female mice in vivo, prompting a reassessment of what "functional gain" means for TREM2 in neurodegeneration.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder. Diffusion tensor imaging (DTI) is widely used to detect brain alterations for diagnosis, but most methods rely on single-scale information. Therefore, this study proposes the multi-view feature learning framework incorporating residual block-based 3D convolutional neural network (3D-CNN) for AD diagnosis. First, tract-based spatial statistics were applied to extract voxel-based features from fractional anisotropy (FA) and...

CONCLUSION: The APP/PS1 mice have a significantly enhanced mechanistic understanding of neuroimmune interactions in AD pathogenesis. Future research should explore microglia-mediated neuroinflammation and brain-gut microbiome interactions to uncover novel diagnostic and therapeutic strategies for AD. This study offers an evidence-based framework to guide researchers using APP/PS1 mice model.

Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer's disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and...

Plasma amyloid-β (Aβ) peptides, alone or in ratio with p-tau217, show strong potential as Alzheimer's disease biomarkers. While immunoprecipitation-mass spectrometry (IP-MS) is the preferred method for plasma Aβ quantification, current assays are resource- and time-intensive. Here, we developed a streamlined IP-MS method using a cost-effective instrument that significantly improved the efficiency of an original assay by incorporating a single immunoprecipitation step, an optimized buffer system,...

No abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory...

Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomics data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) datasets from 84...

Lysosomes maintain a highly acidic lumen to regulate H^(+)-dependent hydrolase-mediated degradation, but how protons are 'leaked' out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2-0.7 pH units more acidic than the...

Neuro- and retinal degenerative diseases, including Alzheimer's, stroke, age-related macular degeneration, and central retinal artery occlusion, rob millions of their independence. Studying these diseases in human retinas has been hindered by the rapid loss of neuronal activity after death. While some CNS activity has been restored postmortem, synchronized neuronal transmission beyond 30 min has remained elusive. We overcome this barrier by reviving and sustaining light signal transmission in...

Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. We present BioPathNet, a graph neural network framework based on the neural Bellman-Ford network (NBFNet), addressing limitations of traditional representation-based learning methods through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns...

Anti-amyloid drugs modestly slow Alzheimer's disease progression, albeit with uncertainty of sustained benefit, particularly as they cause paradoxical acceleration of brain volume changes. Here, we examine explanations for these volume changes and argue for transparent release of clinical trial data.

Although multiple cellular pathways have been implicated in α-Synuclein (α-syn)-associated Parkinson's disease (PD), the role of lipid metabolism remains elusive. In this study, we identify Drosophila mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of α-syn. Silencing the expression of mino significantly suppresses α-syn-induced PD phenotypes in Drosophila, including dopaminergic neuronal loss and...

Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson's Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we employ a fibrillar injection model of enteric synucleinopathy in male mice and demonstrate that ENS-resident...

Emerging evidence implicates the Stuxnet (Stx) protein in human disease, extending beyond its known role in proteasome-independent degradation. Exploring this further, our investigation into stx downstream targets in Drosophila reveals that loss of the U snoRNA host gene 5 (Uhg5) gene disrupts sleep. This sleep phenotype is linked to inefficient translation of mitochondrial genes, as Uhg5 produces small nucleolar RNAs (snoRNAs) that directly regulate mitochondrial transcripts. Using GoldCLIP...

Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and...

Spatial omics links molecular measurements to their positions in tissue, revealing cellular organization and interactions. Yet most computational tools highlight common cell types and overlook rare populations that can drive disease. Here we show GARDEN, a computational framework that identifies and characterizes these pathogenic cells or regions in spatial omics by embedding graph-based dynamic attention into a spatially-aware graph fusion contrastive model. GARDEN works consistently across...

Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer's disease) and alpha-synuclein in Parkinson's disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental...

Parkinson's disease (PD) is a chronic neurological disorder characterized by loss of body movement control due to dopamine abnormalities. PD leads to various pathological symptoms, including muscle stiffness, bradykinesia, tremors, and postural disturbances. As a severe disease, PD caused approximately 329,000 deaths worldwide in 2019. However, PD treatment is very challenging; thus, alternative therapeutic strategies are in high demand. The primary therapeutic hurdle in PD therapy is the...

Parkinson's Disease (PD) is a neurodegenerative disorder primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to classical motor symptoms such as tremors, rigidity, and bradykinesia. In later stages, patients frequently develop non-classical symptoms, including respiratory dysfunctions, which may result from neurodegeneration in brainstem regions involved in respiratory control, such as the pre-Bötzinger Complex (preBötC) and the retrotrapezoid...