Tackling Alzheimer's Disease by Targeting Oxidative Stress and Mitochondria

Studies on pathogenesis of Alzheimer's disease (AD) are centered on amyloid-β (Aβ) toxicity, due in large part to the existence of rare Mendelian conditions that involve amyloid-β precursor protein (AβPP), or components of the γ-secretase complex (presenilins) that process AβPP to produce Aβ. Therapeutic trials targeting Aβ and associated hallmark lesions, however, have failed over many attempts in the past 15years. The failures may be attributed to late administration of therapy relative to disease progression, or more likely to the narrowness of a construct based on pathogenic mutation, which does not address the complexity of sporadic AD. Lessons from preclinical and clinical studies revealed that oxidative stress and mitochondrial abnormalities occur early during the pathological course of AD, representing attractive therapeutic targets to counteract this devastating neurodegenerative disease. In this sense, the chapter provides an overview on the role of oxidative stress and mitochondrial bioenergetics and dynamics to AD pathology. From a therapeutic perspective, the chapter also intends to clarify whether and how oxidative stress and mitochondria can be targeted in order to efficaciously halt or postpone AD-related symptomatic and neuropathological features.