Alzheimer & Parkinson
Can We Fix America's Dementia Care Crisis before It's Too Late?
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The Vexing Promise of New Blood Tests for Alzheimer's
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The Hidden Link between Racism and Alzheimer's Risk
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Controversial New Alzheimer's Drugs Offer Hope-But at a High Cost
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Alzheimer's Drugs Are Finally Tackling the Disease Itself. Here's How
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Can Diet and Exercise Really Prevent Alzheimer's?
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New Hope in Alzheimer's Research
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Employing deep mutational scanning in the <em>Escherichia coli</em> periplasm to decode the thermodynamic landscape for amyloid formation
Deep mutational scanning (DMS) assays provide a powerful method to generate large-scale datasets essential for advancing AI-driven predictions in biology. The tripartite β-lactamase assay (TPBLA), in which a protein of interest is inserted between two domains of β-lactamase, has previously been reported as capable of detecting and quantitating the aggregation of proteins and biologics in the oxidizing periplasm of Escherichia coli and used as a platform for identifying small molecule inhibitors...
Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium...
Sex- and APOE Genotype-Dependent Pain Susceptibility and Alzheimer's Risk Mediated by the Lipid Metabolism Enzyme LPCAT2
Neuropathological changes that precede or accompany early cognitive decline in Alzheimer's disease (AD) may also impact pain processing; however, the molecular connection between these domains remains unclear. In this study, we investigated whether a shared causal factor underlies both increased pain susceptibility and AD progression. Analysis of two ethnically distinct cohorts revealed a significant association between pain susceptibility and cognitive decline from cognitively normal (CN)...
Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C
VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in...
Primary care detection of Alzheimer's disease using a self-administered digital cognitive test and blood biomarkers
After the clinical implementation of amyloid-β-targeting therapies for people with cognitive impairment due to Alzheimer's disease (AD), there is an urgent need to efficiently identify this patient population in primary care. Therefore, we created a brief and self-administered digital cognitive test battery (BioCog). Based on its sub-scores, a logistic regression model was developed in a secondary care cohort (n = 223) and then evaluated in an independent primary care cohort comprising 19...
A review of the TGF-beta1 pathway in Alzheimer's disease and depression: Possible restoration potential of antidepressants
Alzheimer's Disease (AD), the most common type of dementia, is increasing rapidly in prevalence, while Major Depressive Disorder (MDD), the most frequent psychiatric condition, continues to pose significant global healthcare challenges. Recent hypotheses suggest that AD and MDD might be interrelated, potentially sharing common pathophysiological mechanisms. One possible central link is the Transforming Growth Factor-beta 1 (TGF-β1) pathway. Reduced TGF-β1 levels, a cytokine involved in...
A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy
The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases...
Epigenetic mechanisms linking environmental exposure to Parkinson's disease: A comprehensive review
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction and non-motor symptoms affecting cognition, mood and autonomic function. Both genetic susceptibility and environmental exposures such as pesticides (e.g., paraquat, rotenone), heavy metals (e.g., manganese, lead), tobacco smoke, and caffeine have been implicated in PD pathogenesis. Recent studies highlight the role of epigenetic mechanisms including DNA methylation (e.g., SNCA, PARK2), histone...
Temporal biphasic regulation of photoreceptor degeneration by microglial TREM2: A metabolic-immune nexus in retinitis pigmentosa
Retinitis pigmentosa (RP), the leading cause of inherited blindness, lacks therapies because of undefined photoreceptor degeneration mechanisms. While microglia/myeloid cells drive RP progression, their phenotype-regulating determinants remain unclear. Using rd10 mice, we reveal TREM2 as a biphasic RP regulator via STAT2-mediated microglial reprogramming. Early TREM2 loss amplifies neuroinflammation through STAT2 hyperactivation, while late deficiency triggers NF-κB/STAT2-driven microglial...
α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation
α-Synuclein aggregation is a hallmark of Parkinson's disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregation. Intracellular aggregates sequester numerous proteins, including subunits of the endosomal sorting complexes required for transport (ESCRT)-III system for endolysosome membrane repair, but the toxic effects of these events remain poorly understood. Using...
Social exposome and brain health outcomes of dementia across Latin America
A multidimensional social exposome (MSE)-the combined lifespan measures of education, food insecurity, financial status, access to healthcare, childhood experiences, and more-may shape dementia risk and brain health over the lifespan, particularly in underserved regions like Latin America. However, the MSE effects on brain health and dementia are unknown. We evaluated 2211 individuals (controls, Alzheimer's disease, and frontotemporal lobar degeneration) from a non-representative sample across...
Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1
Autophagosome closure by the endosomal sorting complex required for transport (ESCRT) complex is a prerequisite for their dynamin 2 (DNM2)-dependent release from the recycling endosome and subsequent lysosomal clearance. However, the mechanism that coordinates autophagosome closure and release is unknown. We identified that the Alzheimer's disease-associated protein bridging integrator 1 (BIN1) is a critical mediator of this coordination. Prior to autophagosome closure, BIN1 is held at...
Extracellular salt bridge networks around S4 implicated in HCN channel gating and heart disease
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a voltage-gated cation channel that plays a crucial role in regulating cellular excitability, especially in cardiac pacemaker cells and neurons. Its dysregulation is linked to heart diseases such as bradycardia and neurological disorders such as epilepsy, Parkinson's disease, and neuropathic pain. Structural and functional studies have revealed that the S4 voltage sensor of the HCN channel moves downward during...
Alzheimer and Parkinson: Latest results from PubMed
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