Neurotoxic Aβ peptides increase oxidative stress in vivo through NMDA‐receptor and nitric‐oxide‐synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro

Abstract

Beta amyloid (Ab) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Ab to increase oxygen radical production in vivo. The 1±40 Ab fragment increased 2,3-dehydroxybenzoic acid ef¯ux more than the 1±28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Ab peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Ab(25±35) and Ab(35±25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy con®rmed the presence of Ab aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Ab(25±35) but not by Ab(35±25). Neurotoxic Ab peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Ab levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Ab neurotoxicity.

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

“…Several other neurotoxic mechanisms, such as the formation of ionic channels that allows increased calcium uptake by mitochondria and mtPTP opening with subsequent inhibition of respiratory complexes [25], have been proposed for Aβ -induced neurotoxicity that is mediated through intramitochondrial interactions. The fact that Aβ can accumulate both intracellularly and intramitochondrially has been demonstrated by Rosales-Corral et al (2012) [26], in which intracerebral injection of fibrillar Aβ caused accumulation of Aβ both intracellularly and intramitochondrially, deep within the cristae, thereby supporting other investigators' views of intramitochondrial accumulation of Aβ. In addition to inhibiting mitochondrial respiratory complex activities in AD patients, disturbances in mitochondrial dynamics have also been demonstrated.…”

“…This includes disturbances in mitochondrial structure, impairment of dynamin -related peptide (Drp1) and imbalances in fission and fusion, with consequent neuronal damage and synaptic loss [27]. Significant disturbances of mitochondrial proteins and lipids also occur following intramitochondrial accumulation of Aβ, which in turn causes functional impairment of mitochondria in AD [26].…”

Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death

“…Alzheimer's disease is a neurodegenerative disorder characterized by the presence in the brain of senile plaques, containing an amyloid core made of ␤-amyloid peptide (␤A). ␤A is a neurotoxic polypeptide of 39-43 aa that can induce mPTP opening in isolated brain mitochondria (15)(16)(17). Previously, we have shown that addition of ␤A promotes fluctuations of intracellular Ca 2ϩ concentration, and Ca 2ϩ -and CsA-dependent fast, transient mitochondrial depolarizations in astrocytes, indicating activation of PT (18,19).…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Canevari et al, and Casley et al, showed that nonsynaptic brain mitochondria from rats treated with a truncated form of Aβ displayed a specifically complex IV inhibition, whereas other RC complexes remained unaltered (Canevari et al, 1999;Casley et al, 2002). Moreover, Parks et al, reported Aβ-induced complex IV inhibition in rat liver isolated mitochondria (Parks et al, 2001). This complex IV inhibition could lead to further instability or alterations in the assembly of this complex or the respirasome, subsequent alterations in the electron flux, and even increased ROS production due to the backup of reduced complexes upstream in the RC, as mentioned in previous sections.…”