Novel 2H‑Pyrazolo[3,4‑d]thiazole Compounds Targeting NLRP3 for the Treatment of Neurodegenerative Diseases.

Occupational exposures to magnetic fields and neurodegenerative disease risks

The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases.

Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson's disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson's disease and Alzheimer's disease brains versus controls, but they were based on small sample sizes. In this study, we quantified the expression of the most compelling Parkinson's and Alzheimer's disease microRNAs from these meta-analyses ('candidate miRNAs') in one of the largest Parkinson's/Alzheimer's disease case-control post-mortem brain collections available (n = 451), thereby quadruplicating previously investigated sample sizes. Parkinson's disease candidate microRNA hsa-miR-132-3p was differentially expressed in our Parkinson's (P = 4.89E-06) and Alzheimer's disease samples (P = 3.20E-24) compared with controls. Alzheimer's disease candidate microRNAs hsa-miR-132-5p (P = 4.52E-06) and hsa-miR-129-5p (P = 0.0379) were differentially expressed in our Parkinson's disease samples. Combining these novel data with previously published data substantially improved the statistical support (α = 3.85E-03) of the corresponding meta-analyses, clearly implicating these microRNAs in both Parkinson's and Alzheimer's disease. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with α-synuclein neuropathological Braak staging (P = 3.51E-03/P = 0.0117), suggesting that hsa-miR-132-3p/-5p play a role in α-synuclein aggregation beyond the early disease phase. Our study represents the largest independent assessment of recently highlighted candidate microRNAs in Parkinson's and Alzheimer's disease brains, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both Parkinson's and Alzheimer's disease, pinpointing shared pathogenic mechanisms across these neurodegenerative diseases. Intriguingly, based on publicly available high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation data, hsa-miR-132 may interact with SNCA messenger RNA in the human brain, possibly pinpointing novel therapeutic approaches in fighting Parkinson's disease.

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain. Innate immunity-mediated neuroinflammation actively contributes to the onset and progression of neurodegenerative diseases. Inflammasomes are involved in the progression of the innate immune response and are responsible for the maturation of caspase-1 and inflammatory cytokines during neuroinflammation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is one of the most intensively investigated inflammasomes, has been reported to play a key role in neurodegenerative diseases. Here, we reviewed the mechanisms, role, and latest developments regarding the NLRP3 inflammasome with respect to three neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Patient and animal model studies have found that abnormal protein aggregation of Aβ, synuclein, or copper–zinc superoxide dismutase-1 (SOD1), which are the main proteins expressed in the three diseases, respectively, can activate microglial cells, induce increased interleukin-1β (IL-1β) release, and activate the NLRP3 pathway, leading to neurodegeneration. In contrast, a deficiency of the components of the NLRP3 pathway may inhibit Aβ, synuclein, or SOD1-induced microglial activation. These studies indicate a positive correlation between NLRP3 levels and abnormal protein aggregation. However, in the case of ALS, not only microglia but also astrocytes express increased NLRP3 levels and contribute to activation of the NLRP3 pathway. In addition, in this review article, we also focus on the therapeutic implications of targeting novel inhibitors of the NLRP3 inflammasome or of novel drugs that mediate the NLRP3 pathway, which could play a role via NLRP3 in the treatment of neurodegenerative diseases.

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

The Quadrato Motor Training model: implications to the treatment of Alzheimer and Parkinson's disease.

Some philosophical aspects of Alzheimer's discovery: an American perspective.- The aging brain and its disorders.- Epidemiology of Alzheimer's disease.- Descriptive and analytic epidemiology of Alzheimer's disease.- A proposed classification of familial Alzheimer's disease based on analysis of 32 multigeneration pedigrees.- Morphology of Alzheimer's disease and related disorders.- Morphology of white matter, subcortical, dementia in Alzheimer's disease.- Morphology of the cerebral cortex in relation to Alzheimer's dementia.- Quantitative investigations of presenile and senile changes of the human entorhinal region.- Neuronal plasticity of the septo-hippocampal pathway in patients suffering from dementia of Alzheimer type.- Morphology of neurofibrillary tangles and senile plaques.- An in vitro model for the study of the neurofibrillary degeneration of the Alzheimer type.- Molecular and cellular changes associated with neurofibrillary tangles and senile plaques.- Brain abnormalities in aged monkeys: a model sharing features with Alzheimer's disease.- Aged dogs: an animal model to study beta-protein amyloidogenesis.- Immunocytochemical and ultrastructural pathology of nerve cells in Alzheimer's disease and related disorders.- Choline-acetyltransferase immunoreactivity in the hippocampal formation of control subjects and patients with Alzheimer's disease.- Calbindin immunoreactive _eurons in Alzheimer-type dementia.- Lactate production and glycolytic enzymes in sporadic and familial Alzheimer's disease.- Impairment of cerebral glucose metabolism parallels learning and memory dysfunctions after intracerebral streptozotocin.- Choline levels, the regulation of acetylcholine and phosphatidylcholine synthesis, and Alzheimer's disease.- Acetylcholine synthesis and membrane phospholipids.- Hippocampal and cardiovascular effects of muscarinic agents.- Cholinergie and monoaminergic neuromediator systems in DAT. Neuropathological and neurochemical findings.- Alterations in catecholamine neurons in the locus coeruleus in dementias of Alzheimer's and Parkinson's disease.- Tyrosine hydroxylase, tryptophan hydroxylase, biopterin and neopterin in the brains and biopterin and neopterin in sera from patients with Alzheimer's disease.- Postreceptorial enhancement of neurotransmission for the treatment of cognitive disorders.- Excitatory dicarboxylic amino acid and pyramidal neurone neurotransmission of the cerebral cortex in Alzheimer's disease.- The sequence within the two polyadenylation sites of the A4 amyloid peptide precursor stimulates the translation.- Alzheimer-like changes of cortical amino acid transmitters in elderly Down's syndrome.- Characteristics of learning deficit induced by ibotenic acid lesion of the frontal cortex in rats.- Memory loss by glutamate antagonists: an animal model of Alzheimer's disease?.- Convulsant properties of methylxanthines, potential cognitive enhancers in dementia syndromes.- Neurodegenerative diseases: CSF amines, lactate and clinical findings.- Somatostatin-like immunoreactivity and neurotransmitter metabolites in the cerebrospinal fluid of patients with senile dementia of Alzheimer type and Parkinson's disease.- Nerve growth factor in serum of patients with dementia (Alzheimer type).- Neuroendocrine dysfunction in early-onset Alzheimer's disease.- Urinary excretion of salsolinol enantiomers and 1,2-dehydrosalsolinol in patients with degenerative dementia.- Alzheimer's disease - one, two or several?.- Diagnostic criteria of Alzheimer's disease.- Clinical diagnosis of Alzheimer's disease: DSM-III-R, ICD-10 - what else?.- Clinical aspects and terminology of dementing syndromes.- Symptoms of depression in the course of multi-infarct dementia and dementia of Alzheimer's type.- Cognitive deterioration and dementia outcome in depression: the search for prognostic factors.- Diagnostic significance of language evaluation in early stages of Alzheimer's disease.- The Alzheimer patient in the family context: how to help the family to cope.- Towards a clinically specific profile of severe senile primary degenerative dementia of the Alzheimer type (PDDAT).- Sequential clinical approach to differential diagnosis of dementia.- Do old patients with Down's syndrome develop premature brain atrophy?.- Results of EEG brain mapping and neuroimaging methods in Senile Dementia of Alzheimer's Typ (SDAT) and Vascular Dementia (VD).- Regulation of EEG delta activity by the cholinergic nucleus basalis.- EEG- and cognitive changes in Alzheimer's disease - a correlative follow-up study.- Decreased hippocampal metabolic rate in patients with SDAT assessed by positron emission tomography during olfactory memory task.- PET criteria for diagnosis of Alzheimer's disease and other dementias.- Oxygen metabolism in the degenerative dementias.- Positron emission tomography for differential diagnosis of dementia: a case of familial dementia.- Comparison between cerebral glucose metabolism and late evoked potentials in patients with Alzheimer's disease.- High resolution regional cerebral blood flow measurements in Alzheimer's disease and other dementia disorders.- Single photon emission computed tomography (SPECT) in Pick's disease: two case reports.- In vivo studies of hippocampal atrophy in Alzheimer's disease.- Outline for the evaluation of nootropic drugs.- Drug treatment of dementia.- Cognitive enhancing properties of antagonist ?-carbolines: new insights into clinical research on the treatment of dementias?.- Long term treatment of SDAT patients with pyritinol.- Listed in Current Contents.

A Long Shot? Could neurodegenerative disease be caused by a cyanobacterial toxin?

This Special Issue comprises nine reviews offering perspectives from the development of neurodegeneration in different pathologies to neuronal protection, providing new views on the mechanism of neurodegeneration and associated processes and a summary of the progress in neuroscience. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions to The FEBS Journal.

MicroRNAs (miRNA) are small noncoding RNAs that play a significant role in the regulation of gene expression. The literature has explored the key involvement of miRNAs in the diagnosis, prognosis, and treatment of various neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The miRNA regulates various signalling pathways; its dysregulation is involved in the pathogenesis of NDD. The present review is focused on the involvement of miRNAs in the pathogenesis of NDD and their role in the treatment or management of NDD. The literature provides comprehensive and cutting-edge knowledge for students studying neurology, researchers, clinical psychologists, practitioners, pathologists, and drug development agencies to comprehend the role of miRNAs in the NDD's pathogenesis, regulation of various genes/signalling pathways, such as α-synuclein, P53, amyloid-β, high mobility group protein (HMGB1), and IL-1β, NMDA receptor signalling, cholinergic signalling, etc. Methods: The issues associated with using anti-miRNA therapy are also summarized in this review. The data for this literature were extracted and summarized using various search engines, such as Google Scholar, Pubmed, Scopus, and NCBI using different terms, such as NDD, PD, AD, HD, nanoformulations of mRNA, and role of miRNA in diagnosis and treatment. The miRNAs control various biological actions, such as neuronal differentiation, synaptic plasticity, cytoprotection, neuroinflammation, oxidative stress, apoptosis and chaperone-mediated autophagy, and neurite growth in the central nervous system and diagnosis. Various miRNAs are involved in the regulation of protein aggregation in PD and modulating β-secretase activity in AD. In HD, mutation in the huntingtin (Htt) protein interferes with Ago1 and Ago2, thus affecting the miRNA biogenesis. Currently, many anti-sense technologies are in the research phase for either inhibiting or promoting the activity of miRNA. This review provides new therapeutic approaches and novel biomarkers for the diagnosis and prognosis of NDDs by using miRNA.

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduces AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS findings show promise. Pre-symptomatic PD: lithium and valproate AMS findings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication (valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD) are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.