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

mTOR as a central regulator of lifespan and aging DOI Creative Commons
David Papadopoli, Karine Boulay, Lawrence Kazak

et al.

F1000Research, Journal Year: 2019, Volume and Issue: 8, P. 998 - 998

Published: July 2, 2019

The mammalian/mechanistic target of rapamycin (mTOR) is a key component cellular metabolism that integrates nutrient sensing with processes fuel cell growth and proliferation. Although the involvement mTOR pathway in regulating life span aging has been studied extensively last decade, underpinning mechanisms remain elusive. In this review, we highlight emerging insights link to various related aging, such as sensing, maintenance proteostasis, autophagy, mitochondrial dysfunction, senescence, decline stem function.

Language: Английский

Citations

360
Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease DOI Open Access

D. Allan Butterfield,

Debra Boyd‐Kimball

Journal of Alzheimer s Disease, Journal Year: 2018, Volume and Issue: 62(3), P. 1345 - 1367

Published: March 13, 2018

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) its earlier stage, amnestic mild cognitive impairment (aMCI). One source oxidative AD aMCI brains that associated with amyloid-β peptide, Aβ 1-42 oligomers. Our laboratory first showed elevated occurred brain regions rich , but not -poor regions, was among to demonstrate peptides led lipid peroxidation (indexed by HNE) brains. Oxidatively modified proteins have decreased function contribute damaged key biochemical metabolic pathways which these normally play a role. Identification oxidatively methods redox proteomics pioneered Butterfield laboratory. Four recurring altered secondary damage from persons AD, aMCI, or Down syndrome are interrelated neuronal death. This “Quadrilateral Neuronal Death” includes altered: glucose metabolism, mTOR activation, proteostasis network, protein phosphorylation. Some even preclinical AD. We opine targeting pharmacologically lifestyle changes potentially may provide strategies slow perhaps one day, prevent, development this devastating dementing disorder. invited review outlines both vitro vivo studies related discusses importance implications some major achievements research.

Language: Английский

Citations

333
Trisomy 21 consistently activates the interferon response DOI Creative Commons
Kelly D. Sullivan, Hannah C Lewis, Amanda A. Hill

et al.

eLife, Journal Year: 2016, Volume and Issue: 5

Published: July 29, 2016

Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of remain ill defined. Using complementary genomics analyses, we identified interferon pathway as major signaling cascade consistently activated by in human cells. Transcriptome analysis revealed activates transcriptional response fibroblast and lymphoblastoid cell lines, well circulating monocytes T Trisomy cells show increased induction interferon-stimulated genes decreased expression ribosomal proteins translation factors. An shRNA screen determined interferon-activated kinases JAK1 TYK2 suppress proliferation fibroblasts, this defect rescued pharmacological JAK inhibition. Therefore, propose activation, likely via gene dosage four receptors encoded on chromosome 21, contributes to many clinical impacts antagonists could have therapeutic benefits.

Language: Английский

Citations

293
Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia DOI Open Access
Ligia J. Domínguez, Nicola Veronese,

Laura Vernuccio

et al.

Nutrients, Journal Year: 2021, Volume and Issue: 13(11), P. 4080 - 4080

Published: Nov. 15, 2021

Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for impairment and dementia is advanced age followed by other determinants such genetic, socioeconomic, environmental factors, including nutrition physical activity. In the next decades, a rise in cases expected due largely aging of world population. There no hitherto effective pharmaceutical therapies treat age-associated dementia, which underscores crucial role prevention. A relationship among diet, activity, lifestyle with function has been intensively studied mounting evidence supporting these development decline chief cause disability globally. Several dietary patterns, foods, nutrients have investigated this regard, some encouraging disappointing results. This review presents current effects components, supplements, sleep social engagement on prevention or delay onset age-related dementia.

Language: Английский

Citations

271
Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases DOI

Nard Kubben,

Tom Misteli

Nature Reviews Molecular Cell Biology, Journal Year: 2017, Volume and Issue: 18(10), P. 595 - 609

Published: Aug. 9, 2017

Language: Английский

Citations

262
Autophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future perspectives DOI Creative Commons
Zhigang Zhang, Xifei Yang, You‐Qiang Song

et al.

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101464 - 101464

Published: Sept. 20, 2021

Alzheimer's disease (AD) is a complex neurodegenerative in the elderly and most common cause of human dementia. AD characterized by accumulation abnormal protein aggregates including amyloid plaques (composed beta-amyloid (Aβ) peptides) neurofibrillary tangles (formed hyper-phosphorylated tau protein). Synaptic plasticity, neuroinflammation, calcium signaling etc. also show dysfunction patients. Autophagy an evolutionarily conserved lysosome-dependent cellular event eukaryotes. It closely linked to modulation metabolism, through which damaged organelles mis-folded proteins are degraded then recycled maintain homeostasis. Accumulating evidence has shown that impaired autophagy contributes pathogenesis. In present review, we highlight role autophagy, bulk selective regulating metabolic circuits We discuss potential future perspectives autophagy-inducing strategies therapeutics.

Language: Английский

Citations

227
miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregationin vivo DOI Open Access
Pascal Y. Smith,

Julia Hernandez-Rapp,

Francis Jolivette

et al.

Human Molecular Genetics, Journal Year: 2015, Volume and Issue: 24(23), P. 6721 - 6735

Published: Sept. 11, 2015

Alzheimer's disease (AD) and related tauopathies comprise a large group of neurodegenerative diseases associated with the pathological aggregation tau protein. While much effort has focused on understanding function tau, little is known about endogenous mechanisms regulating metabolism in vivo how these contribute to disease. Previously, we have shown that microRNA (miRNA) cluster miR-132/212 downregulated such as AD. Here, report deficiency mice leads increased expression, phosphorylation aggregation. Using reporter assays cell-based studies, demonstrate miR-132 directly targets mRNA regulate its expression. We identified GSK-3β PP2B effectors abnormal vivo. Deletion induced expressing or human mutant an effect autophagy dysfunction. Conversely, treatment AD mimics restored part memory metabolism. Finally, miR-212 levels correlated insoluble cognitive impairment humans. These findings support role for regulation pathology humans provide new alternatives therapeutic development.

Language: Английский

Citations

203
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

185
Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss DOI Open Access
Huixia Li, Danhui Li, Zhengmin Ma

et al.

Autophagy, Journal Year: 2018, Volume and Issue: 14(10), P. 1726 - 1741

Published: July 2, 2018

Macroautophagy/autophagy is a highly regulated process involved in the turnover of cytosolic components, however its pivotal role maintenance bone homeostasis remains elusive. In present study, we investigated direct ATG7 (autophagy related 7) during developmental and remodeling stages vivo using osteoblast-specific Atg7 conditional knockout (cKO) mice. cKO mice exhibited reduced mass at both adult age. The trabecular volume was significantly lower than that controls 5 months This phenotype attributed to decreased osteoblast formation matrix mineralization, accompanied with an increased osteoclast number extent surface covered by osteoclasts as well elevated secretion TNFSF11/RANKL (tumor necrosis factor [ligand] superfamily, member 11), decrease TNFRSF11B/OPG receptor 11b [osteoprotegerin]). Remarkably, deficiency osteoblasts triggered endoplasmic reticulum (ER) stress, whereas attenuation ER stress administration phenylbutyric acid abrogated ablation-mediated effects on differentiation, mineralization capacity formation. Consistently, impeded promoted apoptosis partially DDIT3/CHOP (DNA-damage-inducible transcript 3)- MAPK8/JNK1 (mitogen-activated protein kinase 8)-SMAD1/5/8-dependent manner vitro, while reconstitution could improve restore skeletal balance. conclusion, our findings provide evidences autophagy plays crucial roles regulation suggest innovative therapeutic strategy against diseases.

Language: Английский

Citations

176