α-Synuclein is a presynaptic protein abundant in the cytoplasmic compartment of neurons, whereas its presence in the extracellular space has also been observed under physiological conditions. ...Extracellular α-synuclein has pathological significance, exhibiting cellular toxicity and impairment of synaptic transmission. Notably, misfolded α-synuclein drives the cell-to-cell propagation of pathology via the extracellular space. However, the primary mechanism that regulates the extracellular levels of α-synuclein remains to be determined.
Using several mechanistically distinct methods to modulate neuronal/synaptic activities in primary neuronal culture and in vivo microdialysis, we examined the involvement of neuronal/synaptic activities on α-synuclein release.
We demonstrate here that physiological release of endogenous α-synuclein highly depends on intrinsic neuronal activities. Elevating neuronal activity rapidly increased, while blocking activity decreased, α-synuclein release. In vivo microdialysis experiments in freely moving mice revealed that ~ 70% of extracellular α-synuclein arises from neuronal activity-dependent pathway. Selective modulation of glutamatergic neurotransmission altered extracellular α-synuclein levels, implicating this specific neuronal network in the mechanism of activity-dependent release of α-synuclein. While neuronal activity tightly regulated α-synuclein release, elevated synaptic vesicle exocytosis per se was capable to elicit α-synuclein release. We also found that extracellular α-synuclein exists as high molecular weight species.
The present study uncovers a novel regulatory pathway associated with α-synuclein release, whose dysregulation might affect various pathological actions of extracellular α-synuclein including its trans-synaptic propagation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds ...soluble forms of amyloid, did not improve cognition or functional status.
Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model
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; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .
In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than ...placebo, including skin cancers and infections.
Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro,
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but Notch and other transmembrane proteins are also substrates for γ-secretase,
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and studies have raised concern that the inhibition of γ-secretase could . . .
Abstract Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) was launched in 2008, aiming at conducting a longitudinal workup of a standardized neuroimaging, biomarker and ...clinico-psychological surveys. The research protocol was designed to maximize compatibility with that of US-ADNI, including structural magnetic resonance imaging analysis for the evaluation of brain atrophy, fluorodeoxyglucose and amyloid positron emission tomography, cerebrospinal fluid sampling, APOE genotyping, together with a set of clinical and psychometric tests that were prepared to achieve the highest compatibility to those used in the United States. Japanese ADNI has recruited ∼357 participants (142 amnestic mild cognitive impairment, ∼134 normal aged and 72 mild Alzheimer's disease (AD), as of April 15, 2010). World-wide ADNI activities will establish the rigorous quantitative descriptions of the natural course of AD in its very early stages. The data, as well as the methodologies and infrastructures, will facilitate the clinical trials of disease-modifying therapies for AD using surrogate biomarkers.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and ...the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The leucine-rich repeat kinase 2 (
), the most common causative gene for autosomal-dominant familial Parkinson's disease, encodes a large protein kinase harboring multiple characteristic domains. ...LRRK2 phosphorylates a set of Rab GTPases in cells, which is enhanced by the Parkinson-associated LRRK2 mutations. Accumulating evidence suggests that LRRK2 regulates intracellular vesicle trafficking and organelle maintenance including Golgi, endosomes and lysosomes. Furthermore, genetic knockout or inhibition of LRRK2 cause lysosomal abnormalities in rodents and primates, and cells from Parkinson's patients with LRRK2 mutations also exhibit altered lysosome morphology. Cell biological studies on LRRK2 in a diverse cellular context further strengthen the potential connection between LRRK2 and regulation of the endolysosomal system, part of which is mediated by Rab phosphorylation by LRRK2. We will focus on the latest advances on the role of LRRK2 and Rab in relation to the endolysosomal system, and discuss the possible link to the pathomechanism of Parkinson's disease.
Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids ...including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.
•A survey was carried out on facial nerve palsy following administration of COVID-19 mRNA vaccines.•Data were evaluated statistically using VAERS, a large self-reporting database.•Significantly high ...reporting was observed (reporting odds ratios: 1.84 and 1.54).•The current results need to be validated in future observational studies.
Objectives: Facial nerve palsy (or Bell's palsy) has occasionally been reported following the administration of coronavirus disease 2019 (COVID-19) mRNA vaccines (BNT162b2 and mRNA-1273). Our study investigated such cases using a large self-reporting database from the USA (Vaccine Adverse Event Reporting System VAERS).
Methods: A disproportionality analysis, adjusted for age and sex, was conducted for VAERS reports from individuals who were vaccinated at the age of 18 years or over, between January 2010 and April 2021.
Results: The analysis revealed that the adverse events following immunization (AEFI) of facial nerve palsy, after administration of COVID-19 mRNA vaccines, was significantly highly reported, both for BNT162b2 (reporting odds ratio ROR 1.84; 95% confidence interval CI 1.65–2.06) and mRNA-1273 (ROR 1.54; 95% CI 1.39–1.70). These levels were comparable to that following influenza vaccination reported before the COVID-19 pandemic (ROR 2.04; 95% CI 1.76–2.36).
Conclusions: Our pharmacovigilance study results suggest that the incidence of facial nerve palsy as a non-serious AEFI may be lower than, or equivalent to, that for influenza vaccines. This information might be of value in the context of promoting worldwide vaccination, but needs to be validated in future observational studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the major genetic cause of autosomal-dominantly inherited Parkinson's disease. LRRK2 is implicated in the regulation of intracellular ...trafficking, neurite outgrowth and PD risk in connection with Rab7L1, a putative interactor of LRRK2. Recently, a subset of Rab GTPases have been reported as substrates of LRRK2. Here we examine the kinase activity of LRRK2 on Rab7L1 in situ in cells. Phos-tag analyses and metabolic labeling assays revealed that LRRK2 readily phosphorylates Golgi-localized wild-type Rab7L1 but not mutant forms that are distributed in the cytoplasm. In vitro assays demonstrated direct phosphorylation of Rab7L1 by LRRK2. Subsequent screening using Rab7L1 mutants harboring alanine-substitution for every single Ser/Thr residue revealed that Ser72 is a major phosphorylation site, which was confirmed by using a phospho-Ser72-specific antibody. Moreover, LRRK2 pathogenic Parkinson mutants altogether markedly enhanced the phosphorylation at Ser72. The modulation of Ser72 phosphorylation in Rab7L1 resulted in an alteration of the morphology and distribution of the trans-Golgi network. These data collectively support the involvement of Rab7L1 phosphorylation in the LRRK2-mediated cellular and pathogenetic mechanisms.
•Rab7L1 is identified as a bona fide substrate of LRRK2.•Ser72 is a major in-cell phosphorylation site of Rab7L1.•Parkinson's-linked mutations in LRRK2 increase the Ser72 phosphorylation of Rab7L1.•Rab7L1 phosphorylation at Ser72 modifies the trans-Golgi morphology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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Trial of Solanezumab in Preclinical Alzheimer’s Disease Sperling, Reisa A.; Donohue, Michael C.; Raman, Rema ...
New England journal of medicine/The New England journal of medicine,
09/2023, Volume:
389, Issue:
12
Journal Article
Peer reviewed
Open access
In cognitively normal persons with brain amyloid deposition, solanezumab (an antibody targeting monomeric amyloid) did not slow cognitive decline as compared to placebo over a period of 4.5 years.
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