Alzheimer’s disease as a chronic maladaptive polyamine stress response

Abstract

Polyamines are nitrogen-rich polycationic ubiquitous bioactive molecules with diverse evolutionary-conserved functions. Their activity interferes with numerous genes' expression resulting in cell proliferation and signaling modulation. The intracellular levels of polyamines are precisely controlled by an evolutionary-conserved machinery. Their transient synthesis is induced by heat stress, radiation, and other traumatic stimuli in a process termed the polyamine stress response (PSR). Notably, polyamine levels decline gradually with age; and external supplementation improves lifespan in model organisms. This corresponds to cytoprotective and reactive oxygen species scavenging properties of polyamines. Paradoxically, age-associated neurodegenerative disorders are characterized by upsurge in polyamines levels, indicating polyamine pleiotropic, adaptive, and pathogenic roles. Specifically, arginase overactivation and arginine brain deprivation have been shown to play an important role in Alzheimer’s disease (AD) pathogenesis. Here, we assert that a universal short-term PSR associated with acute stimuli is beneficial for survival. However, it becomes detrimental and maladaptive following chronic noxious stimuli, especially in an aging organism. Furthermore, we regard cellular senescence as an adaptive response to stress and suggest that PSR plays a central role in age-related neurodegenerative diseases' pathogenesis. Our perspective on AD proposes an inclusive reassessment of the causal relationships between the classical hallmarks and clinical manifestation. Consequently, we offer a novel treatment strategy predicated upon this view and suggest fine-tuning of arginase activity with natural inhibitors to preclude or halt the development of AD-related dementia.

Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism

“…Short-term PSR has been proposed to be universally beneficial to the organism's survival [10,11]. Consequently, we suggest that arginase elevation is the first step in a typical PSR that has evolved as a ubiquitous adaptive mechanism.…”

“…Recently, we proposed that short-term PSR associated with acute stimuli is beneficial for survival [10]. In this study, we further developed this hypothesis and applied an arginase inhibitor, norvaline, to treat acute hypoxia in zebrafish (Fig.…”

“…This procedure also inhibits oxidative stress in aging mice [8]. Accordingly, particular scientific attention is attracted to arginase and polyamines as evolutionarily conserved interrelated factors combating oxidative stress [10]. Various stimuli provoke a coordinated cellular stress program accompanied by an upsurge in polyamine levels referred to as the polyamine stress response (PSR) [11].…”

“…An arginase product, ornithine, is a substrate for Odc. Though, a unique subcellular localization, high inducibility, and several regulation levels provide arginases with a paramount ability to control the polyamine synthesis rate [10]. It is notable that Arg1 and arginine decarboxylase (Adc) show similar patterns of distribution in neurons [23], which points to a possible alternative route of polyamine synthesis in the brain via agmatine.…”

Towards a Consensus on Alzheimer’s Disease Comorbidity?

“…Early symptoms of AD include difficulty in remembering recent events, and gradually, bodily functions are lost, ultimately leading to death [ 3 ]. The cause of AD is poorly understood, and some of the risk factors are believed to be inherited, involving multiple genes [ 4 ]. Recently, we have provided new perspectives on AD as a brain expression of complex metabolic disorders [ 5 ].…”