Impaired Adaptive Cellular Responses to Oxidative Stress and the Pathogenesis of Alzheimer's Disease

Abstract

As is generally true with other age-related diseases, Alzheimer's disease (AD) involves oxidative damage to cellular components in the affected tissue, in this case the brain. The causes and consequences of oxidative stress in neurons in AD are not fully understood, but considerable evidence points to important roles for accumulation of amyloid b-peptide upstream of oxidative stress and perturbed cellular Ca 2+ homeostasis and energy metabolism downstream of oxidative stress. The identification of mutations in the b-amyloid precursor protein and presenilin-1 as causes of some cases of early onset inherited AD, and the development of cell culture and animal models based on these mutations has greatly enhanced our understanding of the AD process, and has greatly expanded opportunities for preclinical testing of potential therapeutic interventions. In this regard, and of particular interest to us, is the elucidation of adaptive cellular stress response pathways (ACSRP) that can counteract multiple steps in the AD neurodegenerative cascades, thereby limiting oxidative damage and preserving cognitive function. ACSRP can be activated by factors ranging from exercise and dietary energy restriction, to drugs and phytochemicals. In this article we provide an overview of oxidative stress and AD, with a focus on ACSRP and their potential for preventing and treating AD. Antioxid. Redox Signal. 14, 1519-1534.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…The gist of the cumulative data is that (1) hallmarks of aging promote amyloidogenic APP processing and Tau pathology, (2) Aβ and Tau accumulations accelerate hallmarks of aging, and (3) there is no common linear pathway to synaptic dysfunction and neuronal death in AD. For indepth information on the roles of different hallmarks of brain aging in AD and related dementias, we refer the reader to the following review articles: oxidative stress (Texel and Mattson, 2011), mitochondrial dysfunction (Mattson et al, 2008; DuBoff et al, 2013), impaired autophagy (Nixon, 2013; Kerr et al, 2017), impaired DNA repair (Madabhushi et al, 2014; Leandro et al, 2015), aberrant neuronal network excitability (Palop and Mucke, 2016; Vossel et al, 2017), impaired adaptive stress response signaling (Stranahan and Mattson, 2012), dysregulated neuronal Ca 2+ homeostasis (Bezprozvanny and Mattson, 2008; Stutzmann and Mattson, 2011), impaired energy metabolism (Dauncey, 2014), neuroinflammation (Heppner et al, 2015), and stem cell deficits (Lazarov et al, 2010). Due to space limitations, in this section we describe one specific example of how oxidative damage, impaired autophagy, Ca 2+ dyshomeostasis, and aberrant neuronal network activity can interact reciprocally with Aβ pathology to cause synaptic dysfunction and neuronal death in AD.…”

Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways

“…These studies highlight the need to elucidate age-dependent factors and mechanisms, such as a decline in 20S proteasome adaptation, that contribute to disease in order to promote health span, alleviate the economic problems of the growing aging population, and the potential burden on society. Because the ability to mount homeostatic adaptive responses declines with age, resulting in the decline of overall protein homeostasis (Calderwood et al, 2009; Rattan, 2008; Texel and Mattson, 2011), measuring the adaptive response to oxidative stress and the elimination of damaged proteins by the 20S proteasome may potentially provide useful biomarkers and prognostic data to streamline therapeutics for aging patients.…”

Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

“…Both levels of BDNF and its receptor TrkB decrease with age and these reductions correlate with impaired memory and dendritic spine density among hippocampal neurons [68]. In addition, AHN markedly declines with age and aging has also been reported to be a major contributor to the reduced proliferation of NSCs [66].…”