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

Abstract

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

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

“…Energy deficiency and mitochondrial dysfunction have been recognized as a prominent, early event in AD, but the mechanisms leading to mitochondrial failure are not well understood (15,(17)(18)(19)(20)(21)(22)(23)(24). Recently, we had shown in vivo that P301L mutant tau was capable of inducing mitochondrial dysfunction and increasing levels of ROS in pR5 mice (4).…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Amyloid plaques composed of Aβ-peptides and neurofibrillary tangles containing hyper-phosphorylated Tau are central to the pathology of AD, and both Aβ and Tau have been linked to mitochondrial fission. Degradation of Aβ in a cell line overexpressing amyloid precursor protein (APP) prevents mitochondrial fragmentation (Wang et al, 2008). Conversely, introduction of Aβ into a neuroblastoma cell line causes mitochondrial fission (Manczak et al, 2010).…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Finally, Drp1 was reported to interact and colocalize with Aβ monomers and oligomers in human and mice AD brains, interactions that increase with disease progression , thus supporting a direct role of Aβ on Drp1 pathological modifications. Also, in several models of AD, such as fibroblasts from AD patients, Aβ and APP-treated cells, and transgenic mice, altered mitochondrial distribution and fragmentation of the mitochondrial network were reported to occur due to alterations in Drp1 levels and other proteins involved in mitochondrial dynamics (Wang et al, 2008;Liu et al 2010;Calkins et al, 2011). Another potential mechanism that can cause mitochondrial network alterations in AD is an altered mitochondrial movement.…”