<p>Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics</p>

International Journal of Nanomedicine, Journal Year: 2019, Volume and Issue: Volume 14, P. 5541 - 5554

Published: July 1, 2019

Abstract: Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (∼131 million) by 2050. Alzheimer's disease (AD) one of the major causative factors induce progressive dementia. AD a neurodegenerative disease, its pathogenesis has been attributed extracellular aggregates amyloid β (Aβ) plaques intracellular neurofibrillary tangles made hyperphosphorylated τ-protein in cortical limbic areas human brain. It characterized memory loss neurocognitive dysfunction. The anomalous processing APP β-secretases γ-secretases leads production Aβ 40 42 monomers, which further oligomerize aggregate into senile plaques. also intensifies through infectious agents like HIV. Additionally, during pathogenesis, presence high concentrations peptides central nervous system initiates microglial infiltration. Upon coming vicinity Aβ, microglia get activated, endocytose contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against aggregation. In addition detailed report on leading AD, present review discusses current state art therapeutics diagnostics, including labeling imaging techniques employed as contrast for better visualization sensing points an urgent need nanotechnology efficient therapeutic strategy bioavailability drugs system. Keywords: beta, amyloidogenesis, precursor proteins, β-secretases, γ-secretases, tau phosphorylation

Language: Английский

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The Gut Microbiota and Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2017, Volume and Issue: 58(1), P. 1 - 15

Published: March 31, 2017

The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various disorders but also central nervous system such as Alzheimer's disease (AD). AD, the most common form dementia, i s neurodegenerative disorder associated with impaired cognition cerebral accumulation amyloid-β peptides (Aβ). Most notably, microbiota-gut-brain axis is bidirectional communication fully understood, includes neural, immune, endocrine, metabolic pathways. Studies germ-free animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal transplantation suggest role for host AD-related pathogenesis. increased permeability blood-brain barrier induced by dysbiosis may mediate affect AD pathogenesis other disorders, especially those aging. In addition, bacteria populating can secrete large amounts amyloids lipopolysaccharides, which might contribute modulation signaling pathways production proinflammatory cytokines AD. Moreover, imbalances induce inflammation obesity, type 2 diabetes mellitus, purpose this review summarize discuss current findings elucidate development Understanding underlying mechanisms provide new insights into novel therapeutic strategies

Language: Английский

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Microbiota-Brain-Gut Axis and Neurodegenerative Diseases

Current Neurology and Neuroscience Reports, Journal Year: 2017, Volume and Issue: 17(12)

Published: Oct. 17, 2017

Language: Английский

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Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease

ACS Nano, Journal Year: 2016, Volume and Issue: 10(2), P. 2860 - 2870

Published: Feb. 4, 2016

Mitochondrial oxidative stress is a key pathologic factor in neurodegenerative diseases, including Alzheimer's disease. Abnormal generation of reactive oxygen species (ROS), resulting from mitochondrial dysfunction, can lead to neuronal cell death. Ceria (CeO2) nanoparticles are known function as strong and recyclable ROS scavengers by shuttling between Ce(3+) Ce(4+) oxidation states. Consequently, targeting ceria selectively mitochondria might be promising therapeutic approach for diseases. Here, we report the design synthesis triphenylphosphonium-conjugated that localize suppress death 5XFAD transgenic disease mouse model. The mitigate gliosis morphological damage observed these mice. Altogether, our data indicate potential candidate

Language: Английский

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Current state of Alzheimer’s fluid biomarkers

Acta Neuropathologica, Journal Year: 2018, Volume and Issue: 136(6), P. 821 - 853

Published: Nov. 28, 2018

Alzheimer's disease (AD) is a progressive neurodegenerative with complex and heterogeneous pathophysiology. The number of people living AD predicted to increase; however, there are no disease-modifying therapies currently available none have been successful in late-stage clinical trials. Fluid biomarkers measured cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development establishing personalized medicine approach diagnosis treatment. Biomarkers used programmes should be qualified specific context use (COU). These COUs include, but not limited to, subject/patient selection, assessment state and/or prognosis, mechanism action, dose optimization, response monitoring, efficacy maximization, toxicity/adverse reactions identification minimization. core CSF Aβ42, t-tau, p-tau recognized by research guidelines their diagnostic utility being considered qualification subject selection However, need better understand potential other COUs, as well identify additional reflecting aspects Several novel proposed, role pathology yet validated. In this review, we summarize some the pathological mechanisms implicated sporadic highlight data several established (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, NF-L) associated each mechanism. We discuss biomarker.

Language: Английский

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Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 14(1), P. 22 - 39

Published: Dec. 15, 2017

Language: Английский

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Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Journal of Neurochemistry, Journal Year: 2016, Volume and Issue: 138(6), P. 785 - 805

Published: June 23, 2016

Abstract Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system adjust behavior environmental stimuli control body functions, memories, emotions. Thus, optimal synaptic communication is required for proper brain physiology, slight perturbations synapse function can lead disorders. In fact, increasing evidence has demonstrated relevance dysfunction as a major determinant many neurological diseases. This notion led concept synaptopathies diseases with defects shared pathogenic features. this review, which was initiated at 13th International Society Neurochemistry Advanced School, we discuss basic concepts structure function, provide critical view how aberrant physiology may contribute neurodevelopmental disorders (autism, Down syndrome, startle disease, epilepsy) well neurodegenerative (Alzheimer Parkinson disease). We finally appropriateness potential implications gathering under single term. Understanding common causes intrinsic differences in disease‐associated could offer novel clues toward synapse‐based therapeutic intervention neuropsychiatric image Review, ( ISN ) (Alzheimer's Parkinson's diseases), gathered together term synaptopathies. Read Editorial Highlight article on page 783 .

Language: Английский

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The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: April 25, 2018

Amyloid-ß (Aß) is best known as the misfolded peptide that involved in pathogenesis of Alzheimer's disease (AD), and it currently primary therapeutic target attempts to arrest course this disease. This notoriety has overshadowed evidence Aß serves several important physiological functions. present throughout lifespan, been found all vertebrates examined thus far, its molecular sequence shows a high degree conservation. These features are typical factor contributes significantly biological fitness, suggestion supported by functions beneficial for brain. The putative roles include protecting body from infections, repairing leaks blood-brain barrier, promoting recovery injury, regulating synaptic function. Evidence these comes vitro vivo studies, which have shown cellular production rapidly increases response challenge often diminishes upon recovery. further adverse outcomes clinical trials attempted deplete order treat AD. We suggest anti-Aß therapies will produce fewer effects if triggers deposition (e.g. pathogens, hypertension diabetes) addressed first.

Language: Английский

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Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease

Nature Communications, Journal Year: 2015, Volume and Issue: 6(1)

Published: Nov. 9, 2015

The age-dependent deposition of amyloid-β peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark Alzheimer's disease (AD). Despite age being the greatest risk factor for AD, molecular mechanisms linking ageing to APP processing are unknown. Here we show that asparagine endopeptidase (AEP), pH-controlled cysteine proteinase, activated during and mediates proteolytic processing. AEP cleaves at N373 N585 residues, selectively influencing amyloidogenic fragmentation APP. in normal mice an manner, strongly 5XFAD transgenic mouse model human AD brains. Deletion or APP/PS1 decreases senile plaque formation, ameliorates synapse loss, elevates long-term potentiation protects memory. Blockade cleavage by alleviates pathological behavioural deficits. Thus, acts as δ-secretase, contributing pathogenic AD.

Language: Английский

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Implications of GABAergic Neurotransmission in Alzheimer’s Disease

Frontiers in Aging Neuroscience, Journal Year: 2016, Volume and Issue: 8

Published: Feb. 23, 2016

Alzheimer's disease (AD) is characterized pathologically by the deposition of -amyloid peptides (A) and accumulation neurofibrillary tangles (NFTs) composed hyper-phosphorylated tau. Regardless pathological hallmarks, synaptic dysfunction widely accepted as a causal event in AD. Of two major types synapses CNS: glutamatergic GABAergic, which provide excitatory inhibitory outputs respectively, abundant data implicate an impaired system during progression. However, emerging evidence supports notion that disrupted default neuronal network underlies memory, alterations GABAergic circuits, either plays primary role or compensatory response to excitotoxicity, may also contribute AD disrupting overall function. The goal this review overview involvement A, tau apoE4, genetic risk factor late-onset AD, neurotransmission potential modulating function therapy.

Language: Английский

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