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Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

Zoe L. Hawking

University of Sunderland, Sunderland SR1 3 SD, UK


13 Apr 2016


28 Sept 2016


29 Dec 2016






β-amyloid, acetylcholine, mitochondria, MitoQ, antioxidants, reactive oxygen species (ROS)


Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD. As these drugs simply delay the onset of symptoms, the development of new therapies is key. As neurons are highly energy-demanding cells, they rely heavily on the functions of mitochondria, and any dysfunction affecting respiratory processes can be devastating and lead to the neuronal death characteristic of AD. Dysfunction in fission and fusion processes of mitochondria have been observed in early AD and are heavily involved in AD pathogenesis. Beta-amyloid (Aβ) is a neurotoxic protein formed in the AD brain as a result of inappropriate secretase activity and is one of the major hallmarks of the disease. Aβ has recently been discovered in the membranes of mitochondria, disabling many basic respiratory functions. Ongoing research is largely targeted at protecting mitochondria from damage caused by factors such as Aβ and oxidative stress. Antioxidants have been meticulously studied, and several generic antioxidants such as α-tocopherol have been found to significantly slow the rate of cognitive decline in both mild to moderate and severe AD. MitoQ is a mitochondria specific antioxidant which is able to enter mitochondria in an almost thousand fold greater concentration than is achieved by generic antioxidants. This enables protection against potentially devastating factors for mitochondria, such as lipid peroxidation, oxidative stress and Aβ neurotoxicity. This review further discusses mitochondrial therapies as well as other new treatments for AD.

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