Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

Devi, Latha; Prabhu, Badanavalu M.; Galati, Domenico F.; Avadhani, Narayan G.; Anandatheerthavarada, Hindupur K.

doi:10.1523/jneurosci.1469-06.2006

Cited by 721 publications

(619 citation statements)

References 58 publications

Supporting

Mentioning

584

Contrasting

Unclassified

Order By: Relevance

“…Mitochondria have been shown to interact with aggregation-prone proteins, including α-synuclein and Aβ. More specifically, Aβ has been shown to be localized on the mitochondrial membrane in a transmembrane arrested form, possibly disrupting protein import into the mitochondria (78,79).…”

Section: Discussion Specific Components Of the Protein Homeostasis Symentioning

confidence: 99%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin-proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease.Alzheimer's disease | protein aggregation | protein homeostasis | supersaturation

show abstract

Section: Discussion Specific Components Of the Protein Homeostasis Symentioning

confidence: 99%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The proposed mechanisms of complex IV inhibition by Aβ include (i) blockage of mitochondrial import channels by APP to prevent the import of nuclear-encoded complex IV subunits [66], (ii) sequestration of heme by Aβ [67,68] and (iii) interaction between Aβ and Aβ-binding alcohol dehydrogenase (ABAD) [50,69]. The latter two mechanisms have been suggested to promote ROS production.…”

Section: Origins Of Complex IV Defects In Admentioning

confidence: 99%

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

221

146

View full text Add to dashboard Cite

Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

show abstract

“…Quantitative morphometric analysis of mitochondria shows increased abnormal and damaged mitochondria in AD (9,10). Multiple lines of evidence support APP and A␤ as contributing factors to mitochondrial dysfunction in AD: both APP and A␤ are present in mitochondrial membrane and interact with mitochondrial proteins, block mitochondrial import channels, impair mitochondrial transport, disrupt the electron transfer chain, increase ROS levels, and cause mitochondrial damage (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Wang

Siedlak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

750

608

View full text Add to dashboard Cite

Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid ␤ on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that Ϸ40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with ␤-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or A␤-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid ␤ production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.amyloid precursor protein ͉ DLP1 ͉ mitochondrial fragmentation ͉ OPA1 ͉ perinuclear accumulation

show abstract

Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

Cited by 721 publications

References 58 publications

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Contact Info

Product

Resources

About