Abstract
Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal and clinical studies suggests that mitochondria play a critical role in aging, cancer, diabetes and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Several lines of research suggest that mitochondrial oxidative damage is an important cellular change in most late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and age-related diseases. In addition, epigenetic factors and lifestyle activities may contribute to selective disease susceptibility for each of these diseases. This paper discusses research that has elucidated features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases. This paper also discusses mitochondrial abnormalities and potential mitochondrial therapeutics in AD. 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.
Highlights
AD is categorized into two major forms: sporadic AD and familial AD with < 10% of AD cases being familial (Thinakaran, 1999) and showing autosomal-dominant transmission within affected families
Older women are more likely than age-matched men to suffer from metabolic diseases, such as diabetes and obesity that increase their chances of developing AD Most familial AD (fAD) patients have at least one affected first-degree relative, and in 10% to 15% the mode of inheritance is autosomal dominant transmission (Campion et al, 1999; Jarmolowicz et al, 2014). fAD is triggered by gene mutations of amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2)
Additional novel risk loci associated with sporadic AD (sAD) are: sortilin-like receptor 1 (SORL1), triggering receptor expressed on myeloid cells 2 (TREM2), the membrane-spanning 4-domains, subfamily A (MS4A), ATP-binding cassette transporter A1 and A7 (ABCA1 and 7), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and CD33 (Allen et al, 2012)
Summary
Cell-based therapies are a promising alternative currently being developed to enable the reversal of neurodegeneration in AD either directly by replacing injured neuron or indirectly by stimulating neuronal repair via paracrine signaling at the injury site (Baraniak and McDevitt, 2010). Transplantation of NSCs into animal models of neurodegenerative diseases, including AD, increases the total amount of mtDNA, messenger RNA and protein levels of mitochondrial biogenesis-related factors as well as protein levels of mitochondrial fission genes
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