Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches

Frontiers in Cellular Neuroscience, Journal Year: 2014, Volume and Issue: 8

Published: April 22, 2014

Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this are still diffuse, one reasons for delay finding an effective treatment. In search new targets to novel therapeutic avenues, clinical studies patients who used anti-inflammatory drugs indicating a lower incidence AD have been value support neuroinflammatory hypothesis neurodegenerative processes role innate immunity disease. Neuroinflammation appears occur as consequence series damage signals, including trauma, infection, oxidative agents, redox iron, oligomers τ β-amyloid, etc. context, our theory Neuroimmunomodulation focus on link between neuronal brain inflammatory process, mediated by progressive activation astrocytes microglial cells with consequent overproduction proinflammatory agents. Here, we discuss about astrocytic cells, principal agents neuroinflammation development diseases such AD. also evaluated potential relevance natural components, which include curcumin Andean Compound, prevention coadjuvant treatments.

Language: Английский

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Metabolic network failures in Alzheimer's disease: A biochemical road map

Alzheimer s & Dementia, Journal Year: 2017, Volume and Issue: 13(9), P. 965 - 984

Published: March 21, 2017

Abstract Introduction The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, nonprofit organizations to develop new research directions transform our understanding disease (AD) propel the development critically needed therapies. In response their recommendations, big data at multiple levels are being generated integrated study network failures in disease. We used metabolomics as a global biochemical approach identify peripheral metabolic changes AD patients correlate them cerebrospinal fluid pathology markers, imaging features, cognitive performance. Methods Fasting serum samples Neuroimaging Initiative (199 control, 356 mild impairment, 175 participants) were analyzed using AbsoluteIDQ‐p180 kit. Performance was validated blinded replicates, values medication adjusted. Results Multivariable‐adjusted analyses showed that sphingomyelins ether‐containing phosphatidylcholines altered preclinical biomarker‐defined stages, whereas acylcarnitines several amines, including branched‐chain amino acid valine α‐aminoadipic acid, changed symptomatic stages. Several analytes consistent associations Rotterdam, Erasmus Rucphen Family, Indiana Memory Aging Studies. Partial correlation networks constructed for Aβ 1–42 , tau, imaging, provided initial insights disease‐related processes. Coexpression interconnected key effectors Discussion Metabolomics identified disease‐progression‐related changes. Defining during trajectory its relationship clinical phenotypes provides powerful roadmap drug biomarker discovery.

Language: Английский

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Molecular Pathogenesis of Alzheimer's Disease: An Update

Annals of Neurosciences, Journal Year: 2017, Volume and Issue: 24(1), P. 46 - 54

Published: Jan. 1, 2017

Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness usually unaffected. Alzheimer's disease (AD) most common form dementia; symptoms include memory loss, difficulty solving problems, disorientation in time space, among others. The was first described 1906 at conference Tubingen, Germany Alois Alzheimer. One hundred ten years since its documentation, many aspects pathophysiology AD have been discovered understood, however gaps knowledge continue to exist. This literature review summarizes main underlying neurobiological mechanisms AD, including theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, role tau protein, involvement oxidative stress calcium.

Language: Английский

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Natural products as a source of Alzheimer's drug leads

Natural Product Reports, Journal Year: 2010, Volume and Issue: 28(1), P. 48 - 77

Published: Nov. 12, 2010

This review focuses on recent developments in the use of natural products as therapeutics for Alzheimer's disease. The compounds span a diverse array structural classes and are organized according to their mechanism action, with focus primarily major hypotheses. Overall, discusses more than 180 summarizes 400 references.

Language: Английский

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A Randomized Controlled Trial of Multicomponent Exercise in Older Adults with Mild Cognitive Impairment

PLoS ONE, Journal Year: 2013, Volume and Issue: 8(4), P. e61483 - e61483

Published: April 9, 2013

Background To examine the effect of multicomponent exercise program on memory function in older adults with mild cognitive impairment (MCI), and identify biomarkers associated improvement functions. Methodology/Principal Findings Subjects were 100 (mean age, 75 years) MCI. The subjects classified to an amnestic MCI group (n = 50) neuroimaging measures, other before randomization. each randomized either a or education control using ratio 1∶1. exercised for 90 min/d, 2 d/wk, 40 times 6 months. was conducted under multitask conditions stimulate attention memory. attended two classes. A repeated-measures ANOVA revealed that no × time interactions tests brain atrophy patients. sub-analysis patients exhibited significantly better Mini-Mental State Examination (p .04) logical scores .04), reducing whole cortical (p<.05) compared group. Low total cholesterol levels intervention (p<.05), higher level brain-derived neurotrophic factor related improved ADAS-cog (p<.05). Conclusions/Significance results suggested is beneficial improving maintaining general may predict functions Further studies are required determine positive effects Trial Registration UMIN-CTR UMIN000003662 ctr.cgi?function = brows&action = brows&type = summary&recptno = R000004436&language = J.

Language: Английский

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Alzheimer’s Disease

Sub-cellular biochemistry/Subcellular biochemistry, Journal Year: 2012, Volume and Issue: unknown, P. 329 - 352

Published: Jan. 1, 2012

Language: Английский

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Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

Proceedings of the National Academy of Sciences, Journal Year: 2012, Volume and Issue: 109(9), P. 3510 - 3515

Published: Jan. 30, 2012

A 30-d course of oral administration a semipurified extract the root Withania somnifera consisting predominantly withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation β-amyloid peptides (Aβ) oligomers in brains middle-aged old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective reversing deficits load APPSwInd mice (line J20). The temporal sequence involved an increase plasma Aβ decrease brain monomer after 7 d, indicating increased transport from to periphery. Enhanced expression low-density lipoprotein receptor-related protein (LRP) microvessels Aβ-degrading protease neprilysin (NEP) occurred 14–21 d substantial levels. However, significant liver LRP NEP much earlier, at were accompanied by rise sLRP, peripheral sink for Aβ. In WT mice, induced liver, but not brain, decreased Aβ, that sLRP occurring independent concentration could result clearance Selective down-regulation LRP, NEP, abrogated therapeutic effects extract. remarkable effect W. mediated through up-regulation indicates targeting periphery offers unique mechanism reverses pathology seen models.

Language: Английский

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Neuroprotective Mechanisms of Resveratrol in Alzheimer’s Disease: Role of SIRT1

Oxidative Medicine and Cellular Longevity, Journal Year: 2018, Volume and Issue: 2018(1)

Published: Jan. 1, 2018

Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder of the cortex hippocampus, which eventually leads to cognitive impairment. Although etiology AD remains unclear, presence β ‐amyloid (A ) peptides in these learning memory regions hallmark AD. Therefore, inhibition A peptide aggregation has been considered primary therapeutic strategy for treatment. Many studies have shown that resveratrol antioxidant, anti‐inflammatory, neuroprotective properties can decrease toxicity hippocampus patients, promote neurogenesis, prevent hippocampal damage. In addition, antioxidant activity plays an important role neuronal differentiation through activation silent information regulator‐1 (SIRT1). SIRT1 vital growth neurons prevents apoptotic death by deacetylating repressing p53 activity; however, exact mechanisms remain unclear. Resveratrol also anti‐inflammatory effects as it suppresses M1 microglia activation, involved initiation neurodegeneration, promotes Th2 responses increasing cytokines expression. This review will focus on resveratrol, specifically its association with pathophysiology.

Language: Английский

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A Review of Pterostilbene Antioxidant Activity and Disease Modification

Oxidative Medicine and Cellular Longevity, Journal Year: 2013, Volume and Issue: 2013, P. 1 - 15

Published: Jan. 1, 2013

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its benefit possibly contribute valuable clinical effect. Multiple studies have demonstrated activity pterostilbene both vitro vivo models illustrating preventative therapeutic benefits. The been implicated anticarcinogenesis, modulation neurological disease, anti-inflammation, attenuation vascular amelioration diabetes. In this review, we explore properties relationship common disease pathways give summary potential prevention treatment various medical conditions.

Language: Английский

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The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication

The Annual Review of Pharmacology and Toxicology, Journal Year: 2013, Volume and Issue: 54(1), P. 9 - 26

Published: Sept. 9, 2013

The largest innovations within pharmaceutical development come through new compounds that have unique and novel modes of action. These commonly involve expanding the protein space targeted by agents. At present, information about drugs drug targets is available online via public databases such as DrugBank Therapeutic Targets Database. However, this biased, understandably so, toward established drug-target interactions. To gain a better overview drug-targeted portion human proteome directions current development, we developed data set clinical trial interactions based on CenterWatch's Drugs in Clinical Trials Database, one its kind. Our curation identified 475 potentially targets. This review aims to identify trends currently being explored trials.

Language: Английский

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