The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics DOI
Fabio Di Domenico, Eugenio Barone, Marzia Perluigi

et al.

Antioxidants and Redox Signaling, Journal Year: 2016, Volume and Issue: 26(8), P. 364 - 387

Published: Sept. 14, 2016

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as metabolic disease, characterized by reduced insulin-stimulated growth survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, altered protein homeostasis. Recent Advances: Reduced glucose utilization metabolism have been associated buildup amyloid-β peptide hyperphosphorylated tau, OS, accumulation unfolded/misfolded proteins. Mammalian target rapamycin (mTOR), which aberrantly activated since early stages, plays key role during neurodegeneration by, on side, inhibiting signaling negative feedback mechanism and, other regulating homeostasis (synthesis/clearance).It likely concomitant mutual alterations metabolism-mTOR signaling-protein might represent self-sustaining triangle harmful events trigger degeneration death neurons development progression AD. Intriguingly, cross-talk between components such death, beyond altering redox neuron, further exacerbated levels OS impair pathways involved. Redox proteomic studies human samples animal models AD-like dementia led to identification oxidatively modified composing therefore revealing crucial fueling this aberrant vicious cycle.The compounds able restore function targeted damage valuable therapeutic approach slow or delay Antioxid. Signal. 26, 364-387.

Language: Английский

Ageing as a risk factor for neurodegenerative disease DOI
Yujun Hou, Xiuli Dan, Mansi Babbar

et al.

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(10), P. 565 - 581

Published: Sept. 9, 2019

Language: Английский

Citations

2410
mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies DOI Creative Commons
Antonella Caccamo, Andrea Magrì, David X. Medina

et al.

Aging Cell, Journal Year: 2013, Volume and Issue: 12(3), P. 370 - 380

Published: Feb. 20, 2013

Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological hyperphosphorylated aggregates to form neurofibrillary tangles. The molecular mechanisms leading accumulation remain unclear more needs be done elucidate them. Age major risk factor for all suggesting that changes contributing the aging process may facilitate represent common across different tauopathies. Here, we use multiple animal models complementary genetic pharmacological approaches show mammalian target rapamycin (mTOR) regulates phosphorylation degradation. Specifically, genetically increasing mTOR activity elevates endogenous mouse levels phosphorylation. Complementary it, further demonstrate pharmacologically reducing signaling with ameliorates pathology associated behavioral deficits model overexpressing mutant human tau. Mechanistically, provide compelling evidence association between linked GSK3β autophagy function. In summary, facilitates pathology, while pathology. Given overwhelming increases lifespan healthspan, data presented here have profound clinical implications tauopathies basis how contribute Additionally, these results preclinical indicating valid therapeutic approach

Language: Английский

Citations

328
The mTOR signalling cascade: paving new roads to cure neurological disease DOI
Peter B. Crino

Nature Reviews Neurology, Journal Year: 2016, Volume and Issue: 12(7), P. 379 - 392

Published: June 24, 2016

Language: Английский

Citations

312
mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy DOI
Marzia Perluigi, Fabio Di Domenico,

D. Allan Butterfield

et al.

Neurobiology of Disease, Journal Year: 2015, Volume and Issue: 84, P. 39 - 49

Published: March 29, 2015

Language: Английский

Citations

293
Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease DOI Open Access
P. Hemachandra Reddy,

XiangLing Yin,

Maria Mańczak

et al.

Human Molecular Genetics, Journal Year: 2018, Volume and Issue: 27(14), P. 2502 - 2516

Published: April 24, 2018

The purpose of our study was to determine the toxic effects hippocampal mutant APP (mAPP) and amyloid beta (Aβ) in human mAPP complementary DNA (cDNA) transfected with primary mouse neurons (HT22). Hippocampal tissues are best source studying learning memory functions patients Alzheimer's disease (AD) healthy controls. However, investigating immortalized that express AD proteins provide an excellent opportunity for drug testing. Using quantitative reverse transcriptase-polymerase chain reaction, immunoblotting & immunofluorescence transmission electron microscopy, we assessed messenger RNA (mRNA) protein levels synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic MAP2 number length mAPP-HT22 cells Swedish/Indiana mutations. Mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity adenosine triphosphate. Increased mRNA fission genes, Drp1 Fis1 decreased fusion (Mfn1, Mfn2 Opa1) biogenesis (PGC1α, NRF1, NRF2 TFAM), autophagy (ATG5 LC3BI, LC3BII), mitophagy (PINK1 TERT, BCL2 BNIPBL), synaptic (synaptophysin PSD95) (MAP2) genes were found relative WT-HT22 cells. Cell survival significantly reduced GTPase-Drp1 enzymatic increased Transmission microscopy revealed numbers These findings suggest accumulation Aβ is responsible abnormal dynamics defective MAP2, spines structural functional changes observations strongly causes mitochondrial, autophagy/mitophagy abnormalities neurons, leading neuronal dysfunction.

Language: Английский

Citations

255
Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth DOI Creative Commons
Bodo C. Melnik, Swen Malte John, Gerd Schmitz

et al.

Nutrition Journal, Journal Year: 2013, Volume and Issue: 12(1)

Published: July 25, 2013

Milk has been recognized to represent a functionally active nutrient system promoting neonatal growth of mammals. Cell is regulated by the nutrient-sensitive kinase mechanistic target rapamycin complex 1 (mTORC1). There still lack information on mechanisms mTORC1 up-regulation milk consumption. This review presents as materno-neonatal relay functioning transfer preferential amino acids, which increase plasma levels glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), insulin, hormone (GH) and insulin-like factor-1 (IGF-1) for activation. Importantly, exosomes, regularly contain microRNA-21, most likely genetic transfection enhancing mTORC1-driven metabolic processes. Whereas human breast ideal food infants allowing appropriate postnatal species-specific programming, persistent high signaling during adolescence adulthood continued cow´s consumption may promote diseases civilization.

Language: Английский

Citations

203
Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches DOI Creative Commons
Rashad Hussain, Hira Zubair, Sarah Pursell

et al.

Brain Sciences, Journal Year: 2018, Volume and Issue: 8(9), P. 177 - 177

Published: Sept. 15, 2018

Regeneration refers to regrowth of tissue in the central nervous system. It includes generation new neurons, glia, myelin, and synapses, as well regaining essential functions: sensory, motor, emotional cognitive abilities. Unfortunately, regeneration within system is very slow compared other body systems. This relative slowness attributed increased vulnerability irreversible cellular insults loss function due long lifespan stretch cells cytoplasm over several dozens inches throughout body, insufficiency tissue-level waste removal system, minimal neural cell proliferation/self-renewal capacity. In this context, current review summarized most common features major neurodegenerative disorders; their causes consequences proposed novel therapeutic approaches.

Language: Английский

Citations

194
Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration DOI Creative Commons

Henry Querfurth,

Hankyu Lee

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: July 2, 2021

Abstract Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found the diverse signaling pathways of Mammalian/mechanistic target rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions regulate energy metabolism and support neuronal growth plasticity. However, Alzheimer’s disease (AD), alternately plays pathogenic roles by inhibiting both insulin autophagic removal β-amyloid (Aβ) phospho-tau (ptau) aggregates. It also role cerebrovascular dysfunction AD. is serine/threonine kinase residing at core either two multiprotein complexes termed mTORC1 mTORC2. Recent data suggest that their balanced actions have implications for Parkinson's (PD) Huntington's (HD), Frontotemporal dementia (FTD) Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an inhibitor, there are rapalogs having greater tolerability micro delivery modes, hold promise arresting these age dependent conditions.

Language: Английский

Citations

189
The biological pathways of Alzheimer disease: a review DOI Creative Commons
Marco Calabrò, Carmela Rinaldi, Giuseppe Santoro

et al.

AIMS neuroscience, Journal Year: 2020, Volume and Issue: 8(1), P. 86 - 132

Published: Dec. 16, 2020

Alzheimer disease is a progressive neurodegenerative disorder, mainly affecting older people, which severely impairs patients' quality of life. In the recent years, number affected individuals has seen rapid increase. It estimated that up to 107 million subjects will be by 2050 worldwide. Research in this area revealed lot about biological and environmental underpinnings Alzheimer, especially its correlation with β-Amyloid Tau related mechanics; however, precise molecular events pathways behind are yet discovered. review, we focus our attention on mechanics may lie development. particular, briefly describe genetic elements discuss specific processes potentially associated disease.

Language: Английский

Citations

184
Gene therapy for neurodegenerative disorders: advances, insights and prospects DOI Creative Commons
Wei Chen, Yang Hu, Dianwen Ju

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2020, Volume and Issue: 10(8), P. 1347 - 1359

Published: Jan. 31, 2020

Gene therapy is rapidly emerging as a powerful therapeutic strategy for wide range of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's (PD) and Huntington's (HD). Some early clinical trials have failed to achieve satisfactory effects. Efforts enhance effectiveness are now concentrating on three major fields: identification new vectors, novel targets, reliable delivery routes transgenes. These approaches being assessed closely in preclinical trials, which may ultimately provide treatments patients. Here, we discuss advances challenges gene highlighting promising technologies, future prospects.

Language: Английский

Citations

159