Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

Abstract

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid β (Aβ) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.Methodology/Principal FindingsIn the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.Conclusions/SignificanceThese findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology.

Neurovascular function in Alzheimer's disease patients and experimental models

“…It could also elucidate the impact of hyperphosphorylated t and neurofibrillary tangles on basal forebrain cholinergic neurons, which modulate neurovascular coupling. Significant axonal transport deficits and t hyperphosphorylation were reported by Massaad et al (2010) in 8 and 12-to 16-month-old Tg2576 mice. Authors determined axonal transport rates by visualizing the rate of Mn 2 + accumulation in olfactory bulb with magnetic resonance imaging, after application of a manganese chloride (MnCl 2 ) solution to mouse nostrils.…”

Does vascular pathology contribute to Alzheimer changes?

“…ROS alter vascular regulation through processes involving the formation of peroxynitrite from the reaction between nitric oxide (NO) and superoxide radical. Oxidative stress and reactive oxygen species resulting from mitochondrial dysfunction have, consequently, been strongly implicated in brain ageing, AD and VaD [67,68]. Overall, various factors may contribute to a chronic hypoperfusive state leading to microscopic tissue damage and regional specific syndromes (Fig.…”

Axonal Transport Defects in Alzheimer’s Disease

“…One possible pathway that mitochondrial ROS can affect AT is through phosphorylation of tau protein, which returns back to normal with antioxidative modulation. This phosphorylation site is located within the microtubule binding domain of tau [79]. (2) Cyclophilin D (CypD), in the mitochondrial matrix, is a key component of the mitochondrial permeability transition pore (mPTP).…”