Oxidative stress events and neuronal dysfunction in alzheimer’s disease: Focus on APE1/ref-1-mediated survival strategies

Abstract

Alzheimer’s disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (Aβ) in senile plaques and neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins. New findings suggest that oligomeric Aβ is a more toxic species than fibrillar Aβ relevant to AD pathology. Although the molecular mechanism(s) underlying the disease is not identified completely, various factors have been implicated in the development of AD. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD and recognise them as an early event in AD development. Ageing is considered the greatest risk factor for AD and is linked to oxidative stress which causes accumulation of somatic mutations in mitochondrial DNA (mtDNA) over time and leads to genome instability and mitochondrial dysfunction. Recent studies on AD patients and transgenic mouse models suggest that amyloid precursor protein (APP) and Aβ localise to mitochondria, interact with mitochondrial proteins, disrupt electron transport chain (ETC), increases reactive oxygen species (ROS) level, impair axonal mitochondrial trafficking, thus leading to synaptic damage and cognitive decline associated with AD. It is not known whether accumulation of Aβ is the cause or outcome of declining mitochondrial function in AD. In order to counteract oxidative stress and maintain genome integrity, various DNA repair pathways exist, base excision repair (BER) pathway being the predominant pathway for repairing oxidised base lesions in neuronal cells. APE1 is the central enzyme of the BER pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. Newer studies are revealing the role of APE1 in maintenance of mitochondrial genome repair and function. In this scenario, antioxidant-based therapy, which could reduce oxidative stress and modulate the activities of APE1, can serve as effective treatment providing neuroprotection in AD. This book chapter summarises some recent developments in understanding the pathogenesis of AD linking Aβ-induced oxidative stress, mitochondrial dysfunction, role of APE1 and phytochemicals toward AD therapeutics.