The thiol antioxidant lipoic acid and Alzheimer's disease
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory, cognition, and the ability to communicate effectively and carry out daily activities. Despite extensive research into the pathogenesis of AD, a preventative and neuroprotective treatment is not available in clinical practice. In this chapter, evidence is provided to support the proposal that the thiol antioxidant lipoic acid (LA) may fulfill this therapeutic need. Multiple mechanisms are proposed by which LA interferes with AD pathogenesis, including increasing acetylcholine (ACh) production by activation of choline acetyltransferase (ChAT) and increasing glucose uptake, thus supplying more acetyl-CoA for ACh synthesis, and chelation of redox-active transition metals, hence inhibiting the formation of hydroxyl radicals. The most important activities of LA (or specifically its reduced form dihydrolipoic acid) are related to its antioxidant properties. LA is involved in scavenging of reactive oxygen species (ROS), thereby increasing the levels of available reduced glutathione; scavenging of lipid peroxidation products, such as 4-hydroxynonenal (HNE) and acrolein (prop-2-enal); downregulation of redox-sensitive proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) via NF-κB and upregulation of phase II enzymes via NRF-2. Despite these many and varied proposed positive effects, evidence of the clinical benefits of LA in the treatment of dementia is as yet limited. Here only two published studies are highlighted, which show that a daily dosage of 600 mg LA slowed disease progression in patients with mild dementia, but not in patients with moderatae dementia. In addition, a double-blind, placebo-controlled trial with LA in combination with fish oil identified a substantial long-term benefit for AD patients.