Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer’s Disease?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This pathology results from an abnormal deposition of the β-amyloid (Aβ) peptide and the intracellular accumulation of neurofibrillary tangles. Mitochondrial dysfunctions play an important role in the pathogenesis of AD, due to disturbances in the bioenergetic properties of cells. To date, the usual therapeutic drugs are limited because of the diversity of cellular routes in AD and the toxic potential of these agents. In this context, alpha-lipoic acid (α-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of α-LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1β, and IL-6. Regarding the pharmacokinetic profile, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, α-LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging. Thus, this review aimed to describe the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs, as well as report in vitro and in vivo studies that demonstrate the mitochondrial mechanisms of α-LA involved in AD protection.

Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

“…Not only an aromatic structure can perform antioxidant activity scavenging ROS: thanks to its dithiolane ring, α-Lipoic acid [170] can perform redox reactions promoting a reduction of cytotoxic events in vitro and an amelioration of cognitive functions in AD animal models; the first promising results on AD patients have been already obtained in association with other antioxidant compounds but, unfortunately, there are no clinical trials to evaluate efficacy of isolated α-Lipoic acid [171].…”

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…Since DNA methylation is the most studied epigenetic modification, particular emphasis will be given to those food or nutrients endowed with the potential to modulate DNA methylation rather than other epigenetic traits. In addition, although the link between diet and epigenetic mechanisms is more apparent for dietary methyl donors (e.g., folate, choline and betaine) [ 333 , 334 ], it is now widely appreciated that also other dietary molecules can modify the epigenome [ 14 ].…”

“…More, green and black tea, both rich in antioxidants, contain epigallocatechin gallate, which has been shown to indirectly reduce the formation of the amyloid plaques, typical hallmarks of AD. Even eggs, as primary source of numerous nutrients including vitamin B6, vitamin B12, choline and folic acid, may help us to maintain the brain healthy [13][14][15][16][17][18]. Turmeric, a CUR-rich spice responsible for the yellow color of curry, reduces memory deficits caused by AD by blocking the formation of amyloid plaques.…”

Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures

“…ALA is metabolized in different ways when administered to mammals as a dietary supplement in various combinations; the safety of ALA has been demonstrated in numerous clinical studies [ 24 , 25 , 26 ]. A recent review by Dos Santos et al [ 27 ] on the role of ALA in Alzheimer’s disease (AD) assessed the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs that demonstrate the mitochondrial mechanisms of ALA involved in AD protection.…”