Alzheimer & Parkinson

Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in App^(NL-G-F) AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation...

Alzheimer's disease (AD) is the most common type of dementia. Current treatments for AD are inadequate, and there is a need to design preventive strategies that would improve the resistance or resilience to AD pathology. Because aberrant brain DNA methylation (DNAm) is associated with hallmarks of AD, we tested the hypothesis that a nutritional approach using choline, an essential nutrient and methyl donor, would modulate DNAm to ameliorate AD pathologies. Previous studies showed that perinatal...

While preclinical studies suggest that Phosphodiesterase 5 (PDE5) inhibition may reduce cognitive impairment, findings from observational studies on whether PDE5 inhibitors reduce Alzheimer's disease (AD) risk have been inconsistent. We performed a two-sample cis-Mendelian Randomisation (MR) analysis to estimate the causal effect of PDE5 inhibition on AD risk. The analysis was performed across four different genome-wide association studies (GWAS) of AD to enhance reliability through...

No abstract

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, the effects of which can be slowed down by an early and correct diagnosis. Greater diagnostic accuracy depends on a better understanding of the disease. In this regard, electroencephalography is a promising low-cost tool to explore brain activity and support the diagnosis of AD. When analyzing EEG signals, age is a factor that is not usually taken into account despite being one of the main risk factors. In this work,...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, and with advancements in the medical field, Anti-amyloid monoclonal antibodies (AA mAbs) targeting amyloid-β have emerged as potential disease-modifying agents altering AD pathology. This scoping review mapped the characteristics, patterns, and gaps in clinical trials investigating the efficacy and safety of AA mAbs in AD treatments, with focus on cognitive, functional, biochemical, imaging, and...

Low bone mass is frequently observed in Alzheimer's disease (AD), yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that sensory nerves constitute a critical component of the skeletal stem cell (SSC) niche. Deletion of the neurotrophin receptor p75NTR in neurons or sensory-specific cells, but not in osteogenic or sympathetic cells, resulted in reduced sensory innervation, disrupted SSC homeostasis, and significant bone loss. Although a cell-intrinsic role of...

Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by toxic accumulation of misfolded and intrinsically disordered proteins (IDPs) that overwhelm cellular proteostasis. The proteasome clears these proteins, but its failure in disease remains unclear. We engineered a Caenorhabditis elegans model with a hyperactive 20S proteasome (α3ΔN) for selective 20S activation. α3ΔN markedly enhanced IDP and misfolded protein degradation, reduced oxidative damage, and...

Decomposing behavior into elementary components remains a central challenge in computational neuroethology. The current standard in laboratory animals involves multi-view video tracking, which, while providing unparalleled access to full-body kinematics, imposes environmental constraints, is data-intensive, and has limited scalability. We present an alternative approach using inertial sensors, which capture high-resolution, environment-independent, compact 3D kinematic data, and are commonly...

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced...

The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1,...

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a diagnostic challenge due to its asymptomatic early stages and the lack of reliable, non-invasive biomarkers. Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane-bound particles released by cells into biological fluids and have emerged as promising carriers of disease-specific biomarkers. These vesicles reflect the physiological and pathological state of their parental cells,...

Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary...

CONCLUSION: Origanum majorana infusion may enhance or regulate antioxidant status and reduce oxidative damage in patients with PD. Further studies are warranted to explore its potential therapeutic benefits.

Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP^(+)/MPTP...

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and...

Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and...

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that...

Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on...

While progressive cognitive decline is the defining feature of Alzheimer's disease (AD), many patients also develop prominent neuropsychiatric symptoms, including anxiety and depression. The circuit-level mechanisms underlying these distinct symptom domains remain poorly understood, and treatments that address both cognitive and noncognitive aspects of AD are limited. Here, we identify anatomically, molecularly, and functionally distinct subpopulations of supramammillary (SuM) neurons that...