Alzheimer & Parkinson

Alzheimer's disease is now defined by underlying pathology, with elevated amyloid-beta (Aβ) sufficient for diagnosis in the absence of cognitive symptoms. We combined longitudinal magnetic resonance imaging and Aβ positron emission tomography data from three cognitively healthy cohorts to examine cortical thickness trajectories in individuals who later converted to Aβ-positive status, using magnetic resonance images acquired years before conversion. Individuals who subsequently developed...

Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome^(1,2). It can be mitigated by mapping to multiple haplotypes represented in a pangenome^(3-5). Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent-offspring trio data. Using Emblask, we assembled 698...

Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to...

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Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, primarily due to the lack of reliable tools for its early and non-invasive diagnosis. Exosomes, nanosized extracellular vesicles secreted by neural and peripheral cells, have emerged as promising biomarkers reflecting the molecular alterations associated with AD pathogenesis. Fourier Transform Infrared (FTIR) spectroscopy, with its capacity to capture unique biochemical fingerprints of biomolecules,...

Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493...

Synucleinopathies, including idiopathic Parkinson's Disease, are driven by misfolding and aggregation of the 140 residue α-synuclein protein that plays a role in presynaptic vesicle regulation. We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven human A53T α-synuclein directs fully penetrant lethal motor disease. Kcnn1 overexpression increased median survival of these mice...

Alzheimer's disease (AD) is a multifactorial disorder that requires combined therapeutic strategies beyond amyloid clearance. Although GLP-1 receptor agonists show strong mechanistic rationale and supportive epidemiological signals for neuroprotection, large randomized trials in symptomatic AD have yielded negative clinical outcomes and do not support the therapeutic use in AD.

Advanced age is accompanied by progressive metabolic, nutritional, mitochondrial, and neuroimmune dysregulation, which may increase susceptibility to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting the need to identify modifiable mechanisms that influence disease initiation and progression. Increasing evidence indicates that nutrition, sleep, and circadian rhythms function as an interconnected biological network regulating metabolic...

Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation...

Gut motility dysfunction is a common symptom of Parkinson's disease (PD), but its central mechanisms remain unclear. Here, we utilize multiple mouse models, which mimic both genetic and sporadic PD, to reproduce PD-related gut motility dysfunction. We find that α-synuclein pathology significantly impairs the excitability of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic activation of these neurons effectively restores gut motility in PD models, revealing a...

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the...

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2...

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue...

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular...

Graph theory provides unique tools to assess complex networks. It has been previously used with functional magnetic resonance imaging (fMRI) datasets to quantify macroscopic-scale connections among different brain regions, readily capturing brain network changes in subjects with Alzheimer's disease. Here, we apply graph theory to miniscope calcium imaging data recorded from the prefrontal cortex of freely behaving wild-type (WT) and Shank3^(fx) mice (a mouse model of autism) during social...

The choroid plexus (ChP) regulates cerebrospinal fluid homeostasis and immune surveillance, but its cellular organization and response to Alzheimer's disease (AD) remain incompletely defined. Here, we integrate single-nucleus RNA sequencing with spatial transcriptomics to generate a high-resolution atlas of the adult human ChP. We identify all major epithelial, stromal, and immune populations and resolve heterogeneity within macrophages, including a distinct subset expressing the giant protein...

Social interaction regulates neuronal excitability and behavior, and the lateral septum (LS) plays an important role in social behavior. However, the molecular mechanisms that support LS-dependent social responses remain unclear. Here, we show that neuronal activity-driven glucose transporter 4 (GLUT4) plasma translocation in LS GABAergic neurons supports social familiarity. Neuronal activation triggers CaMKIIα-mediated phosphorylation of GLUT4 at Ser243 and Ser254, which enhances Rab10 binding,...

The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and α synucleinopathy models of PD in vitro and in vivo....

Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of...