Alzheimer & Parkinson

No abstract

No abstract

BACKGROUND: Alzheimer's disease neuropathology, characterised by amyloid β (Aβ) and phosphorylated-tau (p-tau) protein accumulation, has primarily been assessed with biomarkers in clinical samples of older adults. Less is known about plasma biomarkers of Alzheimer's disease neuropathology and their associations with cognitive outcomes in midlife in diverse community-based samples. Our goal was to address these gaps.

BACKGROUND: Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection.

BACKGROUND: Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic...

Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting...

Transposable elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact on brain TE RNA dynamics in these phenomena is not fully understood. Therefore, we quantify TE RNA changes in aging postmortem human and mouse brains and in the neurodegenerative disorders Huntington's disease (HD) and Parkinson's disease (PD). We track TE small RNAs (smRNAs) to assess the relationship to TE large RNA (laRNA) expression patterns. Human brain transcriptomes from the BrainSpan Atlas...

No abstract

Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the aggregation of alpha-synuclein (αSyn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of αSyn into aggregates and their...

Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein and include Alzheimer's disease (AD) and related dementia disorders. Identifying new strategies to treat tauopathy remains an important gap in the field. Using forward and reverse genetic approaches in C. elegans, we identified smrd-1, the C. elegans homolog of SMARCAD1, as a potent modifier of tauopathy phenotypes in a transgenic model of tauopathy. Loss of smrd-1 function rescues...

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are key mediators of calcium ion (Ca^(2+)) influx required for proper neuronal function. Excessive NMDAR-mediated Ca^(2+) influx is neurotoxic and associated with neurological disease. Memantine and ketamine, two NMDAR antagonists with overlapping binding sites in the NMDAR channel, are of high clinical interest. Whereas memantine is a well-tolerated Alzheimer's disease medication, ketamine is a fast-acting antidepressant with abuse potential and...

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein. The development of a positron emission tomography tracer to detect aggregates of misfolded α-synuclein could revolutionize early diagnosis, disease monitoring, and the evaluation of therapeutic efficacy. Here, we present the development, preclinical validation, and first-in-human evaluation of [^(11)C]MODAG-005. In vitro binding...

Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain's white matter (WM) microstructure. Here we present a large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N = 54,583...

Selective butyrylcholinesterase (BChE) inhibition is gaining renewed attention as a potential therapeutic strategy for Alzheimer's disease (AD), particularly in advanced stages marked by a shift from acetylcholinesterase (AChE) to BChE dominance. Beyond cholinergic regulation, BChE participates in metabolic, inflammatory, and affective pathways, including the enzymatic control of acyl ghrelin that influences appetite, energy balance, and mood. Preclinical and experimental evidence suggests that...

Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating...

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported...

Endoplasmic reticulum autophagy (ER-phagy) is a selective autophagy pathway in which receptor proteins target ER membranes and proteins for degradation, yet its role in Alzheimer's disease (AD) remains unclear. Here, we identify FAM134B/RETREG1 as a specific ER-phagy receptor mediating amyloid precursor protein (APP) degradation. FAM134B directly interacts with ER-localized wild-type and familial mutant APP via their C-terminal domains and recruits LC3 through its LC3-interacting region (LIR) to...

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and...

Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation,...

Nearly two-thirds of Americans with Alzheimer's disease (AD) are women. Prior research suggested that women with AD have lower brain estrogen levels than those without AD. However, how estrogen deficiency modulates this sex-based difference in AD vulnerability is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, including the hippocampus. This study aims to assess the mechanistic link between brain-selective...