Alzheimer & Parkinson

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with...

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag,...

Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. We identify PLK2 as a crucial early-response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuates LPS-induced expression of proinflammatory factors in microglial cells by suppressing the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ)-nuclear factor (NF)-κB signaling pathway....

α-Synuclein (α-syn), a crucial molecule in Parkinson's disease (PD), is known for its interaction with lipid membranes, which facilitates vesicle trafficking and modulates its pathological aggregation. Deciphering the complexity of the membrane-binding behavior of α-syn is crucial to understand its functions and the pathology of PD. Here, we used single-molecule imaging to show that α-syn forms multimers on lipid membranes with huge intermultimer distances. The multimers are characterized by...

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates...

L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the preferred treatment for Parkinson's Disease (PD) and is considered the gold standard. However, prolonged use of L-DOPA in patients can result in involuntary movements known as Levodopa-induced dyskinesia (LID), which includes uncontrollable dystonia affecting the trunk, limbs, and face. The role of ΔFosB protein, a truncated splice variant of the FosB gene, in LID has been acknowledged, but its underlying mechanism has remained elusive....

The attainable resolution of fluorescence microscopy has reached the subnanometer range, but this technique still fails to image the morphology of single proteins or small molecular complexes. Here, we expand the specimens at least tenfold, label them with conventional fluorophores and image them with conventional light microscopes, acquiring videos in which we analyze fluorescence fluctuations. One-step nanoscale expansion (ONE) microscopy enables the visualization of the shapes of individual...

Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune...

Profiling metagenomes against databases allows for the detection and quantification of microorganisms, even at low abundances where assembly is not possible. We introduce sylph, a species-level metagenome profiler that estimates genome-to-metagenome containment average nucleotide identity (ANI) through zero-inflated Poisson k-mer statistics, enabling ANI-based taxa detection. On the Critical Assessment of Metagenome Interpretation II (CAMI2) Marine dataset, sylph was the most accurate profiling...

The Phase II trial of Anti-alpha-Synuclein Antibody in Early Parkinson's Disease (PASADENA) is an ongoing double-blind, placebo-controlled trial evaluating the safety and efficacy of prasinezumab in early-stage Parkinson's disease (PD). During the double-blind period, prasinezumab-treated individuals showed less progression of motor signs (Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III) than placebo-treated individuals. We...

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the...

Recent research has revolutionized our understanding of memory consolidation by emphasizing the critical role of astrocytes, microglia, and immune cells in through cytokine signaling. Cytokines, compact proteins, play pivotal roles in neuronal development, synaptic transmission, and normal aging. This review explores the cellular mechanisms contributing to cognitive decline in inflammaging and Alzheimer's disease, highlighting the paradoxical effects of most studied cytokines (IL-1, IL-6, TNF-α)...

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The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old...

Vision impairment (VI) and eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and cataract have been reported to be associated with cognitive impairment and dementia, however, to date, very little attempt has been made to collate and synthesizes such literature. Therefore, the aim of this umbrella review is to systematically assesses the credibility and certainty of evidence of associations between vision impairment (VI) and eye diseases with...

Selective vulnerability offers a conceptual framework for understanding neurodegenerative disorders such as Parkinson's disease, where specific neuronal types are selectively affected and adjacent ones are spared. However, the applicability of this framework to neurodevelopmental disorders, particularly those characterized by atypical social behaviors, such as autism spectrum disorder, remains uncertain. Here we show that an embryonic disturbance, known to induce social dysfunction in male mice,...

This study investigates the association between cognitive dysfunction and hippocampal volumes in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) using Mendelian randomization. A meta-analysis of 503 healthy controls, 562 MCI patients, and 389 CE patients revealed significant reductions in hippocampal and subregion volumes in MCI and AD compared to controls. While various subregions showed volume reductions, no causal relationship between hippocampal volume and AD was established...

Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility...

Magnetic resonance angiography (MRA) is pivotal for diagnosing panvascular diseases. However, single-modality MRA falls short in diagnosing diverse vascular abnormalities. Thus, contrast agents combining T(1) and T(2) effects are sought for multiparameter MRA with clinical promise, yet achieving a balance in T(1) and T(2) contrast enhancement effects remains a scientific challenge. Herein, we developed a hypersensitive multiparameter MRA strategy using dual-modality NaGdF(4) nanoparticles....

Agency fines Cassava Sciences $40 million for touting flawed research on simufilam.