Alzheimer & Parkinson

Local protein synthesis (LPS) in axons is now recognized as a physiological process, participating both in the maintenance of axonal function and diverse plastic phenomena. In the last decades of the 20th century, the existence and function of axonal LPS were topics of significant debate. Very early, axonal LPS was thought not to occur at all and was later accepted to play roles only during development or in response to specific conditions. However, compelling evidence supports its essential and...

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus...

We have developed the regionalpcs method, an approach for summarizing gene-level methylation. regionalpcs addresses the challenge of deciphering complex epigenetic mechanisms in diseases like Alzheimer's disease. In contrast to averaging, regionalpcs uses principal components analysis to capture complex methylation patterns across gene regions. Our method demonstrates a 54% improvement in sensitivity over averaging in simulations, providing a robust framework for identifying subtle epigenetic...

Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before,...

The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, ageing-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late-onset neurodegenerative disorders, such as Alzheimer's disease. Accordingly, the maintenance of proteostasis through late stages of life bears the...

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Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts,...

Different forms of phosphorylated tau (p-tau) have shown strong potential as Alzheimer's disease (AD) biomarkers in both cerebrospinal fluid (CSF) and plasma. We hypothesized that p-tau proteoforms simultaneously phosphorylated at two different sites may have an increased diagnostic value compared with tau phosphorylated at a single site. Here, we developed two immunoassays detecting CSF and plasma tau simultaneously phosphorylated at both T181 and T231 (p-tau181&231) and at T217 and T231...

Alzheimer's disease is characterized by progressive amyloid deposition and cognitive decline, yet the pathological mechanisms and treatments remain elusive. Here we report the therapeutic potential of low-intensity 40 hertz blue light exposure in a 5xFAD mouse model of Alzheimer's disease. Our findings reveal that light treatment prevents memory decline in 4-month-old 5xFAD mice and motivation loss in 14-month-old 5xFAD mice, accompanied by restoration of glial water channel aquaporin-4...

Microglia, as resident immune cells in the central nervous system (CNS), play a crucial role in maintaining homeostasis and phagocytosing metabolic waste in the brain. Senescent microglia exhibit decreased phagocytic capacity and increased neuroinflammation through senescence-associated secretory phenotype (SASP). This process contributes to the development of various neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we found that SASP was elevated in senescent...

Vascular dementia (VaD) is a second most common type of dementia subsequent to Alzheimer disease (AD). VaD is characterized by cognitive impairment and memory loss that may progress due to the development of cerebral amyloid angiopathy (CAA) a hallmark of AD. CAA triggers the progression of ischemic and hemorrhagic strokes with the subsequent the development of VaD and mixed dementia. Early diagnosis of patients with appropriate use of anti-inflammatory can prevent CAA-related inflammation and...

Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson's disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing...

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DNA methylation (DNAm) is essential for brain development and function and potentially mediates the effects of genetic risk variants underlying brain disorders. We present INTERACT, a transformer-based deep learning model to predict regulatory variants affecting DNAm levels in specific brain cell types, leveraging existing single-nucleus DNAm data from the human brain. We show that INTERACT accurately predicts cell type-specific DNAm profiles, achieving an average area under the receiver...

The brain of patients with Parkinson's disease (PD) was characterized by increased phosphorylation and oligomerization of α-synuclein (α-syn) and altered activity of enzymes regulating α-syn phosphorylation and oligomerization. Whether increased α-syn phosphorylation and oligomerization as well as related enzyme changes can be detected in the plasma of PD patients remains unclear. Here, we showed that human α-syn proteins incubated in PD plasma formed more oligomerized α-syn (O-α-syn) and...

Loss of Y chromosome (LOY) is the most commonly occurring post-zygotic (somatic) mutation in male individuals. The past decade of research suggests that LOY has important effects in shaping the activity of the immune system, and multiple studies have shown the effects of LOY on a range of diseases, including cancer, neurodegeneration, cardiovascular disease and acute infection. Epidemiological findings have been corroborated by functional analyses providing insights into the mechanisms by which...

Isolated rapid eye movement sleep behavior disorder is a prodrome of α-synucleinopathies. Using positron emission tomography, we assessed changes in Parkinson's disease-related motor and cognitive metabolic networks and caudate/putamen dopaminergic input in a 4-year longitudinal imaging study of 13 male subjects with this disorder. We also correlated times to phenoconversion with baseline network expression in an independent validation sample. Expression values of both Parkinson's...

Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, k(PCr)) is associated with less ventricular enlargement and brain aging progression, and less atrophy...

Neurodegeneration in Huntington's disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinson's and Alzheimer's diseases, the atomic-level structure of HTTex1 fibrils has remained...

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A(2A) receptor. For this, we designed seven photochemical affinity switches derived from the anti-Parkinson's drug istradefylline. In a rational...