Alzheimer & Parkinson

During deep co-evolution of viruses and host cells, viruses have selected specific host cellular proteins redirected from physiological functions to viral needs, thereby disturbing cellular proteostasis and increasing the risk of triggering protein misfolding diseases (PMDs). Identifying virus-specific, repurposed host proteins also allows the study of fundamental cellular events in "sporadic" PMDs, independent of the virus. Here, we identify a small molecule with very strong activity against...

Parkinson's disease (PD) patients show gait and motor timing impairments that can be improved with different behavioral therapies. This study involved an intervention with seventeen PD patients utilizing a pre-training-training-post-training protocol. The experimental paradigm included a march-in-place task (MPT) and an auditory synchronization-continuation stepping task (SCT). During these tasks, their foot movements were tracked with an infrared motion-capture system. In addition, patients...

Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD...

Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in aging. Here we find that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA), which are naturally enriched in black rice, inhibit amyloid pathology, rescue cognition and extend lifespan in mouse preclinical models of Alzheimer's disease via allosteric activation of G protein-coupled receptor 120 (GPR120) in plaque-associated macrophages and activated microglia. We...

Progressive neuronal loss and brain atrophy are principal determinants of cognitive decline in Alzheimer's disease (AD), yet most mouse models fail to recapitulate these features. Here we identify cyclin-dependent kinase 3 (CDK3) as a key driver of neurodegeneration in AD. CDK3 is elevated in human AD brains and correlates with disease severity. As laboratory mice carry a nonfunctional Cdk3 mutation, we generated two models with restored CDK3 activity and then crossed to AD backgrounds. Both...

With therapeutic progress in Alzheimer's disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment...

Genetic variants associated with complex traits often lie in distal enhancers. While candidate enhancers have been mapped genome wide, their functional state and gene targets in specific cell types remain unclear. Here we present AstroREG, a resource of enhancer-gene interactions in human primary astrocytes, generated by combining CRISPR inhibition (CRISPRi), single-cell RNA-seq and machine learning. By functionally testing nearly 1,000 PsychENCODE enhancers, we identified more than 150...

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Synaptic loss is a hallmark of Alzheimer's disease (AD) but lacks robust blood-based biomarkers. We investigate growth-associated protein 43 (GAP-43), previously identified as a synaptic candidate in the cerebrospinal fluid (CSF). Postmortem proteomic profiling of brain-derived extracellular vesicles (n = 21) highlights GAP-43 as a central hub within synaptic protein networks co-depleted in AD and closely linked with proteins enriched in immune-, metabolic-, and synaptic-related modules. In two...

Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce...

The prevalence of Alzheimer's disease neuropathological changes (ADNCs), the leading cause of cognitive impairment, remains uncertain. Recent blood-based biomarkers enable scalable assessment of ADNCs¹. Here we measured phosphorylated tau at threonine 217 in 11,486 plasma samples from a Norwegian population-based cohort of individuals over 57 years of age as a surrogate marker for ADNCs. The estimated prevalence of ADNCs increased with age, from less than 8% in people 58-69.9 years of age to...

Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic...

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Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1)...

Sporadic early-onset Alzheimer's disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight...

When two genes linked to increased Parkinson's risk converge on a lysosome, LRRK2 mutation enhances lysosomal release of soluble GPNMB potentially contributing to synuclein pathology.

Genome-wide association studies have identified Glycoprotein Nmb (GPNMB) as a risk factor for Parkinson's disease. The risk allele increases GPNMB transcription and GPNMB protein levels in the CSF highlighting GPMNB as a potential biomarker for Parkinson's disease. However, a lack of knowledge of GPNMB's function and mechanism of secretion has hindered an interpretation of secreted GPNMB levels. In this study, we assessed the mechanism of GPNMB secretion by macrophages, the primary cell type...

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. In 2024 it affected approximately 1 in 9 people aged 65 and older in the U.S., 6.9 million individuals. Early detection and accurate AD diagnosis are crucial for improving patient outcomes. Magnetic resonance imaging (MRI) has emerged as a valuable tool for examining brain structure and identifying potential AD biomarkers. This study performs predictive analyses by employing...

Alzheimer's disease (AD) is a significant neurological condition that is marked by the gradual decline of memory and cognitive function, with a higher incidence observed in older individuals. The mental deterioration associated with this condition is irreversible, resulting in substantial consequences for both affected individuals and society as a whole. Despite relentless research efforts, a definitive cure for AD remains elusive. However, interventions targeting the early stages of the disease...

Single-cell multiomics provides critical insights into how disease-associated variants identified through genome-wide association studies (GWASs) influence transcription factor eRegulons within a specific cellular context; however, the regulatory roles of genetic variants in aging and disease remain unclear. Here, we present scMORE, a method that integrates single-cell transcriptomes and chromatin accessibility with GWAS summary statistics to identify cell-type-specific eRegulons associated with...