Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: Implications for early intervention and therapeutics

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease affecting thousands of people in the world and effective treatment is still not available. Over two decades of intense research using AD postmortem brains, transgenic mouse and cell models of amyloid precursor protein and tau revealed that amyloid beta (Aβ) and hyperphosphorylated tau are synergistically involved in triggering disease progression. Accumulating evidence also revealed that aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction initiates and contributes to the development and progression of the disease. The purpose of this article is to summarize the latest progress in aging and AD, with a special emphasis on the mitochondria, oxidative DNA damage including methods of its measurement. It also discusses the therapeutic potential of oxidative DNA damage and treatment strategies in AD.

Iron, Aging, and Neurodegeneration

“…The production of reactive oxygen species (ROS) or nitrogen species (RNS) has been linked to changes in the brain associated with normal aging and also to diseases that can occur during aging such as the neurodegenerative diseases [1,2]. For many neurodegenerative diseases, especially the most common ones like Alzheimer's disease and Parkinson's disease, aging is a prerequisite for developing them [3,4]. While we can measure changes in various chemicals or reactions in the brain, the actual mechanism by which growing older makes us more susceptible to neurodegenerative diseases is a mystery.…”

Recent progress and concerns in dementia: Distinguishing Alzheimer's disease and dementia with Lewy bodies via biochemical markers in the cerebrospinal fluid

“…The role of the microtubule-associated protein tau, another hallmark protein, in the pathogenesis of Alzheimer's disease, including tau as a crucial partner of Aβ, as well as their interactions with mitochondria, has also been summarized recently [27,28]. Notably, oxidative damage is thought to be the earliest event in Alzheimer's disease [8,29]. Aβ directly induces reactive oxygen species (ROS) [8], and toxic soluble Aβ oligomers appear to have synaptic receptors colocalizing with PSD-95 (postsynaptic density protein 95), and Aβ42 accumulates in dendrites in AD patients where it may cause oxidative damage and caspase activation and eventually apoptosis [30].…”

“…Recent progress in AD, especially Aβ, mitochondria and oxidative stress related pathology has been reviewed [8,26]. The role of the microtubule-associated protein tau, another hallmark protein, in the pathogenesis of Alzheimer's disease, including tau as a crucial partner of Aβ, as well as their interactions with mitochondria, has also been summarized recently [27,28].…”

“…The etiology of LOAD is much complicated, and age has a significant impact on its development. In pathology, extracellular fibrillar amyloid-β (Aβ), especially long form 42 amino acids of Aβ (Aβ42) deposits in the brain [8,17], intracellular neurofibrillary tangles (NFT) and neuronal as well as axonal degeneration are the main features of the disease. Even fairly accurate, the clinical diagnosis of probable AD based on traditional diagnostic criteria does not take the long preclinical and prodromal course of AD into account.…”

“…In addition, cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage are involved in various neurodegenerative disorders, including AD and DLB [6][7][8]. With increased longevity and increased prevalence of obesity, diabetes, hypertension and other chronic diseases, dementia is likely to raise significantly [9,10].…”