Alzheimer's Disease

New England Journal of Medicine, Journal Year: 2010, Volume and Issue: 362(4), P. 329 - 344

Published: Jan. 27, 2010

This review of Alzheimer's disease assembles a variety findings relevant to the mechanism and ties them together using current understanding basis loss cognition: accumulation misfolded proteins, which cause oxidative inflammatory damage brain and, ultimately, synaptic dysfunction.

Language: Английский

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Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2017, Volume and Issue: 57(4), P. 1105 - 1121

Published: Jan. 6, 2017

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding mechanism hinders development efficacious therapeutic approaches. The loss synapses in affected brain regions correlates best with cognitive impairment patients and has been considered as early that precedes neuronal loss. Oxidative stress recognized contributing factor aging progression multiple diseases including AD. Increased production reactive oxygen species (ROS) associated age- disease-dependent mitochondrial function, altered metal homeostasis, reduced antioxidant defense directly affect synaptic activity neurotransmission neurons leading to dysfunction. In addition, molecular targets by ROS include nuclear DNA, lipids, proteins, calcium dynamics cellular architecture, receptor trafficking endocytosis, energy homeostasis. Abnormal metabolism turn could accumulation amyloid-β (Aβ) hyperphosphorylated Tau protein, which independently exacerbate dysfunction production, thereby vicious cycle. While mounting evidence implicates etiology, clinical trials therapies have not produced consistent results. this review, we will discuss role oxidative AD, innovative strategies evolved based on better complexity mechanisms dual play health disease.

Language: Английский

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Alzheimer's disease: clinical trials and drug development

The Lancet Neurology, Journal Year: 2010, Volume and Issue: 9(7), P. 702 - 716

Published: June 17, 2010

Language: Английский

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Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Proceedings of the National Academy of Sciences, Journal Year: 2009, Volume and Issue: 106(34), P. 14670 - 14675

Published: Aug. 11, 2009

Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial precedes the development of AD pathology, we conducted functional analyses female triple transgenic mice (3xTg-AD) and age-matched nontransgenic (nonTg). 3xTg-AD brain was evidenced by decreased respiration pyruvate dehydrogenase (PDH) protein level activity as early 3 months age. also exhibited increased oxidative stress manifested hydrogen peroxide production lipid peroxidation. amyloid beta (Aβ) significantly at 9 temporally correlated with Aβ binding alcohol (ABAD). Embryonic neurons derived from mouse hippocampus glycolysis. Results these indicate that compromised function is evident embryonic hippocampal neurons, continues unabated females throughout reproductive period, exacerbated during senescence. In control mice, coincident senescence accompanied significant decline function. Reproductive markedly dysfunction. Collectively, data occurs pathogenesis model. provides plausible mechanistic rationale for hypometabolism diagnosis suggests therapeutic targets prevention AD.

Language: Английский

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Delirium

Nature Reviews Disease Primers, Journal Year: 2020, Volume and Issue: 6(1)

Published: Nov. 12, 2020

Language: Английский

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Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 20(13), P. 2495 - 2509

Published: March 31, 2011

The purpose of our study was to better understand the relationship between mitochondrial structural proteins, particularly dynamin-related protein 1 (Drp1) and amyloid beta (Aβ) in progression Alzheimer's disease (AD). Using qRT-PCR immunoblotting analyses, we measured mRNA levels genes frontal cortex patients with early, definite severe AD control subjects. We also characterized monomeric oligomeric forms Aβ these patients. immunoprecipitation/immunoblotting analysis, investigated interaction Drp1. immunofluorescence determined localization Drp1 intraneuronal brains primary hippocampal neurons from precursor (AβPP) transgenic mice. found increased expression fission Fis1 (fission 1) decreased fusion Mfn1 (mitofusin 1), Mfn2 2), Opa1 (optic atrophy Tomm40. matrix gene CypD up-regulated Results analyses suggest that abnormal dynamics increase as progresses. Immunofluorescence analysis antibody antibodies 6E10 A11 revealed colocalization Aβ. interacts monomers oligomers patients, interactions are progression. Primary were accumulated had lost branches degenerated, indicating may cause neuronal degeneration. These findings AD, production crucial factors fragmentation, synaptic damage. Inhibiting, be a therapeutic strategy reduce damage cognitive decline AD.

Language: Английский

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Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

Proceedings of the National Academy of Sciences, Journal Year: 2010, Volume and Issue: 107(32), P. 14164 - 14169

Published: July 26, 2010

Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to autophagy dysfunction are still not clear. Based on results genome-wide screen, we show reactive oxygen species (ROS) serve as common mediators upstream activation type III PI3 kinase, which is critical initiation autophagy. Furthermore, ROS play an function induction kinase and response amyloid β peptide, main pathogenic mediator Alzheimer's disease (AD). lysosomal blockage also caused by Aβ independent ROS. In addition, demonstrate transcriptionally down-regulated during normal aging human brain. Strikingly, contrast aging, observe transcriptional up-regulation brains AD patients, suggesting there might be compensatory regulation Interestingly, drug candidate have inhibitory effects raising possibility decreasing input into system may help reduce stress AD. Finally, provide list targets can used safely modulate levels without causing cell death.

Language: Английский

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Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 20(23), P. 4515 - 4529

Published: Aug. 25, 2011

Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes mitochondrial failure degeneration Alzheimer's disease (AD). The purpose this study was to better understand effects Aβ activity alterations neurons from a mouse model AD. Using primary well-characterized precursor protein transgenic (AβPP) (Tg2576 line), for first time, we studied activity, including axonal transport mitochondria, dynamics, morphology function. Further, also nature Aβ-induced alterations, cell death Tg2576 mice, sought determine whether mitochondria-targeted antioxidant SS31 could mitigate oligomeric Aβ. We found significantly decreased anterograde movement, increased fission fusion, abnormal proteins defective function AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed large number small structurally damaged broken cristae an apoptotic neuronal relative WT Our results intraneuronal Aβ, leading deficiencies, ultimately causing neurodegeneration cultures. However, restored viability, percentage indicating protects toxicity.

Language: Английский

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Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal

Trends in Pharmacological Sciences, Journal Year: 2008, Volume and Issue: 29(12), P. 609 - 615

Published: Oct. 5, 2008

Language: Английский

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Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease

Progress in Neurobiology, Journal Year: 2016, Volume and Issue: 147, P. 1 - 19

Published: Oct. 19, 2016

Language: Английский

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