Alzheimer & Parkinson

α-Synuclein (αSyn) is a presynaptic protein of unestablished physiological function that plays a central role in Parkinson's disease neuropathology. To date, the reported effects of αSyn expression on the kinetics of axonal synaptic vesicle exocytosis and membrane cycling have been relatively small. In contrast, we report that αSyn is the major modulator of substantia nigra somatodendritic dopamine release, a little-understood form of neurotransmission that is central to sensorimotor and basal...

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, BIN1 and RIN3 have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP)...

Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and Alzheimer's disease (AD). In animal models, glymphatic impairment alone can drive AD pathology. Whether this system clears amyloid beta (Aβ) and tau in humans remains unknown. In a randomized crossover trial with 39 participants, we found that glymphatic clearance during normal sleep increased morning plasma levels of AD biomarkers compared to sleep deprivation. Participants underwent...

Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and...

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Alzheimer's disease (AD) remains a major unmet medical challenge, with limited tools that integrate early diagnosis and therapeutic intervention. Considering the pivotal roles of amyloid-β (Aβ) and cholinesterases (ChEs) in AD etiology, we report dual-functional theranostic NIR-I probes. The lead candidate, I-43, exhibits favorable NIR optical properties (Stokes shift ≥ 220 nm) and binds strongly to Aβ fibrils, with K(d) values of 58.2 ± 9.7 nM for Aβ(1-40) and 104 ± 25 nM for Aβ(1-42)....

Although upregulation of toll-like receptor 2 (TLR2) excessively activates pro-inflammatory microglia through Aβ peptides, it remains unclear whether TLR2 regulates neuronal pyroptosis via the NF-κB/NLRP3 pathway in Alzheimer's disease (AD). We assessed TLR2 expression in peripheral blood from clinical samples and employed SH-SY5Y cells for initial screening. AD pathology was simulated by Aβ(1-42) stimulation, and pathway regulatory relationships were dissected through TLR2 knockdown, NF-κB...

CONCLUSIONS: We present a thorough genetic analysis of the relationship between HF, AD, and the intestinal-neuroimmune interaction, emphasizing the potential of GM and immune cells as therapeutic targets.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in...

Alzheimer's disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied. Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on...

Parkinson's disease (PD) pathogenesis is driven by α-synuclein (α-syn) amyloid aggregation, with the flexible C-terminal region mediating pathological interactions with cellular receptors and facilitating disease propagation and neuroinflammation. Through immunization with human α-syn fibrils and iterative neuronal binding and propagation assays, we identify H21 as a high-affinity fibril-specific monoclonal antibody. H21 selectively binds to α-syn fibrils and specifically targets the C-terminal...

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,...

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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...