Alzheimer & Parkinson

Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from...

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Sexual dysfunction (SD) is a common non-motor symptom in Parkinson's disease (PD) that substantially reduces patients' quality of life. However, the underlying neural mechanisms of SD in PD remain poorly understood. This study aimed to investigate the role of functional abnormalities in brain regions with dopaminergic innervation in male PD patients with SD, using resting-state functional magnetic resonance imaging (rs-fMRI). A total of 34 male PD patients were enrolled. The bilateral caudate,...

The associations of β-amyloid (Aβ) and tau deposition with white matter (WM) degeneration in Alzheimer's disease (AD) remain inadequately elucidated. We investigate baseline and longitudinal changes of microstructural fractional anisotropy (FA) and macrostructural white matter hyperintensities (WMHs) and their relationships with Aβ and tau positron emission tomography (PET) and vascular risk factors in different Aβ/tau stages defined by PET imaging. Lower levels and faster decline rates of FA...

The sense of smell is essential for human perception. Olfactory function declines with increasing age, affecting a substantial portion of the elderly population, and this decline is more pronounced in men. This reduction can be attributed to anatomical and degenerative changes in the brain and olfactory receptors. There is robust clinical evidence indicating an association between olfactory perception decline/deficit (OPD) and major neurodegenerative diseases, with severe deficits observed in...

Alzheimer's disease (AD) and traumatic brain injury (TBI) are currently untreatable neurodegenerative disorders afflicting millions of people worldwide. These conditions are pathologically related, and TBI is one of the greatest risk factors for AD. Although blood-brain barrier (BBB) disruption drives progression of both AD and TBI, strategies to preserve BBB integrity have been hindered by lack of actionable targets. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme...

Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a...

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A (CgA) knockout (CgA-KO) mice. CgA is known to be associated with protein aggregates in the brains of neurodegenerative diseases including Alzheimer's disease (AD). Here, we investigated the role of CgA in Tau pathogenesis in AD and corticobasal degeneration (CBD). CgA ablation in Tauopathy mice (PS19) (CgA-KO/PS19)...

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in...

Ferritins are ubiquitous proteins that function in iron storage/detoxification by catalyzing the oxidation of Fe^(2+) ions and solubilizing the resulting Fe^(3+)-oxo mineral. Mammalian tissues that are metabolically highly active contain, in addition to the widespread cytosolic ferritin, a ferritin that is localized to mitochondria. Mitochondrial ferritin (FtMt) protects against oxidative stress and is found at higher levels in diseases associated with abnormal iron accumulation, including...

Proteomic studies have been instrumental in identifying brain, cerebrospinal fluid and plasma proteins associated with Alzheimer's disease (AD). Here, we comprehensively examined 6,905 aptamers corresponding to 6,106 unique proteins in plasma in more than 3,300 well-characterized individuals to identify new proteins, pathways and predictive models for AD. We identified 416 proteins (294 new) associated with clinical AD status and validated the findings in two external datasets representing more...

Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD...

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Over the recent years, numerous research efforts have been focused toward xanthones, a class of heterocyclic compounds characterized by a three-ring core structure and a diverse range of biological activities. Despite extensive studies, no xanthone-based molecule has successfully progressed through clinical trials to reach pharmaceutical applications. Xanthones belong to the class of secondary metabolites that exist naturally, found in various plant species, and their structural diversity has...

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial...

Neuroinflammation contributes to the loss of dopamine neurons and motor dysfunctions in Parkinson's disease (PD). How cell metabolism regulates neuroinflammation by modulating epigenetic modifications is largely unknown. In this study, we found that the expression of phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first step of the de novo serine synthesis pathway was mainly expressed in astrocytes and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) injection triggered the...

Both neuronal and peripheral tissues become disrupted in Alzheimer's disease (AD). However, a comprehensive understanding of how AD impacts different tissues across the whole organism is lacking. Using Drosophila, we generated an AD Fly Cell Atlas (AD-FCA) based on whole-organism single-nucleus transcriptomes of 219 cell types from flies expressing AD-associated proteins, either human amyloid-β 42 peptide (Aβ42) or Tau, in neurons. We found that Aβ42 primarily affects the nervous system,...

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The expression level of α-synuclein is thought to play a crucial role in the pathogenesis of Parkinson's disease. However, little is known about the molecular mechanisms regulating the transcription of its gene, SNCA, particularly in the context of the disease. The transcription factor ZSCAN21 has been shown to act on SNCA, but whether ZSCAN21 is actually involved in the induction of SNCA transcription in Parkinson's disease is unknown. To address this question, we used the MPTP mouse model and...

Glycosphingolipids (GSLs) are important targets in immune, infectious, lysosomal storage diseases, cancer, and neurodegenerative diseases. Circulatory GSLs profiling in clinical samples is restricted by the lack of mid- and high-throughput analytical methods and deep coverage of long-chain sialylated glycosphingolipidome. We present a 4-dimensional (4D)-glycosphingolipidomics platform for routine glycosphingolipidome profiling encompassing: extraction and fractionation of sialylated GSLs with 3...