Amyloid-β-Induced Mitochondrial Dysfunction Impairs the Autophagic Lysosomal Pathway in a Tubulin Dependent Pathway

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

Journal of Neuroinflammation ◽

10.1186/s12974-021-02099-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Andre F. Batista ◽

Tayná Rody ◽

Leticia Forny-Germano ◽

Suzana Cerdeiro ◽

Maria Bellio ◽

...

Keyword(s):

Cognitive Impairment ◽

Mitochondrial Dysfunction ◽

Memory Impairment ◽

Mitochondrial Dynamics ◽

Interleukin 1 ◽

Amyloid Β ◽

Mitochondrial Fusion ◽

Synapse Loss ◽

Cynomolgus Macaques ◽

The Impact

Abstract Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

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MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

International Journal of Molecular Medicine ◽

10.3892/ijmm.2018.3957 ◽

2018 ◽

Cited By ~ 11

Author(s):

Fang‑Zhou Chen ◽

Ying Zhao ◽

Hui‑Zhao Chen

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Mitochondrial Dysfunction ◽

Notch Signaling ◽

Signaling Pathway ◽

Protein Production ◽

Amyloid Β ◽

Notch Signaling Pathway ◽

Amyloid Β Protein ◽

Β Protein

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Amyloid-β-Induced Mitochondrial Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-2007-12208 ◽

2007 ◽

Vol 12 (2) ◽

pp. 177-184 ◽

Cited By ~ 62

Author(s):

John Xi Chen ◽

Shi Du Yan

Keyword(s):

Mitochondrial Dysfunction ◽

Amyloid Β

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Correction to: Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca2+-dependent pathway in mouse Neuro-2a neuroblastoma cells

APOPTOSIS ◽

10.1007/s10495-018-1492-5 ◽

2018 ◽

Vol 24 (1-2) ◽

pp. 198-199

Author(s):

Ji Hyun Choi ◽

Jung Yeon Lee ◽

A-Young Choi ◽

Keun-Young Hwang ◽

Wonchae Choe ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Mitochondrial Dysfunction ◽

Neuroblastoma Cells ◽

Phospholipase Cγ1 ◽

Dependent Pathway

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Amyloid-β, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs?

Neurochemistry International ◽

10.1016/s0197-0186(01)00123-1 ◽

2002 ◽

Vol 40 (6) ◽

pp. 527-531 ◽

Cited By ~ 50

Author(s):

M Smith

Keyword(s):

Alzheimer Disease ◽

Mitochondrial Dysfunction ◽

Amyloid Β

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Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00001.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. H475-H484 ◽

Cited By ~ 39

Author(s):

Pallabi Sarkar ◽

Ivan Zaja ◽

Martin Bienengraeber ◽

Kevin R. Rarick ◽

Maia Terashvili ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Rat Brain ◽

Clinical Symptoms ◽

Mitochondrial Dynamics ◽

Amyloid Β ◽

Cellular Respiration ◽

Epoxyeicosatrienoic Acids ◽

Hippocampal Astrocytes

Amyloid-β (Aβ) has long been implicated as a causative protein in Alzheimer's disease. Cellular Aβ accumulation is toxic and causes mitochondrial dysfunction, which precedes clinical symptoms of Alzheimer's disease pathology. In the present study, we explored the possible use of epoxyeicosatrienoic acids (EETs), epoxide metabolites of arachidonic acid, as therapeutic target against Aβ-induced mitochondrial impairment using cultured neonatal hippocampal astrocytes. Inhibition of endogenous EET production by a selective epoxygenase inhibitor, MS-PPOH, caused a greater reduction in mitochondrial membrane potential in the presence of Aβ (1, 10 μM) exposure versus absence of Aβ. MS-PPOH preincubation also aggravated Aβ-induced mitochondrial fragmentation. Preincubation of the cells with either 14,15- or 11,12-EET prevented this mitochondrial depolarization and fragmentation. EET pretreatment also further improved the reduction observed in mitochondrial oxygen consumption in the presence of Aβ. Preincubation of the cells with EETs significantly improved cellular respiration under basal condition and in the presence of the protonophore, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). The uncoupling of ATP synthase from the electron transfer chain that occurred in Aβ-treated cells was also prevented by preincubation with EETs. Lastly, cellular reactive oxygen species production, a hallmark of Aβ toxicity, also showed significant reduction in the presence of EETs. We have previously shown that Aβ reduces EET synthesis in rat brain homogenates and cultured hippocampal astrocytes and neurons (Sarkar P, Narayanan J, Harder DR. Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain. Neuroscience 194: 241–249, 2011). We conclude that reduction of endogenous EETs may be one of the mechanisms through which Aβ inflicts toxicity and thus supplementing the cells with exogenous EETs improves mitochondrial dynamics and prevents metabolic impairment.

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