Alzheimer & Parkinson

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and aggregation of α-Synuclein (α-Syn). While both genetic and environmental factors are implicated in PD pathogenesis, the mechanisms underlying neurodegeneration induced by environmental toxins and associated genetic responses remain largely unknown. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to be a critical mediator of toxin-induced motor...

Despite genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci^(1-3), the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent...

Path integration, the ability to track one's position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer's disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer's disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path...

Dynamic changes in dopamine, noradrenaline, and serotonin release are believed to causally contribute to the neural computations that support reward-based decision making. Accordingly, changes in signaling by these systems are hypothesized to underwrite multiple cognitive and behavioral symptoms observed in many neurological disorders. Here, we characterize the release of these neurotransmitters measured concurrently in the caudate of patients with Parkinson's disease or essential tremor...

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Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer's disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model (App^(NL-F/NL-F)). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their...

The "gut-brain axis" is an emerging target in Alzheimer's disease (AD), although its immunological features remain poorly understood. Using single-cell RNA sequencing, coupled to extensive spectral-tuning flow cytometry validation of the colon immune compartment in the 5XFAD amyloid-β mouse model, we found several AD-associated changes including in B/plasma cell activity. Notably, levels of CXCR4^(+) antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating...

Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of...

Age-related hearing loss (ARHL) has emerged as a significant and potentially modifiable risk factor for neurodegenerative disorders, including Alzheimer's disease. A growing body of evidence links ARHL to structural and functional changes in the brain, with implications for cognitive decline and dementia onset. However, both ARHL and dementia are multifactorial conditions shaped not only by biological mechanisms but also by broader social determinants of health. Inequities in access to hearing...

Amyloid-β (Aβ), a key driver of Alzheimer's disease (AD) pathogenesis, possesses diverse harmful and clearance-resistant structures that present substantial challenges to therapeutic development. Here, we demonstrate that modulating Aβ morphology, rather than Toll-like receptor 2 (TLR2)-dependent microglia activation, is essential for effective phagocytosis of Aβ species by microglia. By developing a bifunctional mechanistic probe (P2CSKn) designed to remodel Aβ and activate TLR2, we show it...

Lactate is the end product of anaerobic glycolysis. Its functions in the central nervous system have garnered increasing attention as new roles continue to emerge. Beyond serving as an energy source and a substrate for gluconeogenesis, lactate also functions as a signaling molecule that regulates diverse cellular activities. Recent studies have demonstrated that lactate contributes to protein lactylation-a novel posttranslational modification-and plays a crucial role in metabolic reprogramming....

Early detection of Alzheimer's disease remains complex and costly despite advancements in neurobiological markers. We propose an innovative approach based on the topological and kinetic analysis of verbal exchanges to distinguish patients from healthy individuals. Without requiring full transcription, we leverage a convolutional network capable of identifying discursive patterns indicative of cognitive impairments. Our experiments, conducted with 80 participants, demonstrate performance levels...

Cerebrospinal fluid (CSF) total tau (t-tau) is considered a biomarker of neuronal degeneration alongside brain atrophy and fluid neurofilament light chain protein (NfL) in biomarker models of Alzheimer's disease (AD). However, previous studies show that CSF t-tau correlates strongly with synaptic dysfunction/degeneration biomarkers like neurogranin (Ng) and synaptosomal-associated protein 25 (SNAP25). Here, we compare the association between CSF t-tau and synaptic degeneration and...

Amyloid β (Aβ)-dependent circuit dysfunction in Alzheimer's disease (AD) is determined by a puzzling mix of hyperactive and inactive ("silent") brain neurons. Recent studies identified excessive glutamate accumulation as a key Aβ-dependent determinant of hyperactivity. The cellular mechanisms underlying neuronal silence depend on both Aβ and tau protein pathologies, with an unknown role of Aβ. Here, by using single-cell-initiated rabies virus (RV) tracing in mouse models of β-amyloidosis, we...

Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity - they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein-protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer's disease. This review explores how PTMs within...

MAPT/tau proteins propagate between brain regions in a prion-like manner, driving the onset and progression of dementia in Alzheimer disease (AD). However, the basis for variability in dementia progression among AD patients remains poorly understood. Here, we demonstrate that cognitively resilient AD patients, characterized by reduced MAPT/tau pathology, maintain lysosomal integrity, whereas cognitively vulnerable patients, exhibiting greater MAPT/tau burden, display lysosomal dysfunction....

Prefibrillar structures of the amyloid-β (Aβ) peptide are central to cytotoxicity in Alzheimer's disease. Time-resolved imaging of oligomers has enabled quantification of their extension. A snapshot of these prefibrillar assemblies has been characterized using a combination of cryo-electron tomography (cryo-ET), cryo-electron microscopy (cryo-EM) single-particle analysis, and atomic force microscopy (AFM). A highly consistent diameter for all curvilinear protofibrils and oligomers of 2.8...

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. We conducted a biobank-scale study to (i) identify endocrine, nutritional, metabolic, and digestive disorders with potential causal or temporal associations with AD/PD risk before diagnosis; (ii) assess plasma biomarkers' specificity for AD/PD in the context of co-occurring gut related traits and disorders; and (iii) integrate multimodal datasets to enhance AD/PD prediction. Our findings...

The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231...

The upregulation of transmembrane protein 175 (TMEM175) has the potential to improve Parkinson's disease (PD) by aiding in the removal of α-synuclein aggregates. Understanding the structural basis of TMEM175 agonisms is crucial for uncovering its therapeutic potential for PD. Here, we have identified the first cryo-electron microscopy (cryo-EM) structure of human TMEM175 complexes with three agonists: DCY1020, DCY1040, and TUG-891. An open state of TMEM175 is unequivocally captured, laying the...