A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Polis, Baruh; Samson, Abraham O.

doi:10.15586/alzheimersdisease.2019.ch1

“…Additionally, metabolomics studies of human plasma clearly indicate differentially affected polyamine and arginine metabolism in AD patients. As a result, the subjects with MCI are easily distinguishable from healthy controls and AD patients [ 163 ], which gives hope for AD diagnosis at early stages with routine laboratory blood tests and further supports our perspective on AD as a brain expression of a complex metabolic disorder [ 146 ].…”

Section: Polyamine Pathway In Alzheimer’s Diseasementioning

confidence: 89%

“…Several definite hallmarks of the disease have been described and studied with precision, however, the causal relationships between them and clinical dementia remain to be revealed. Mounting evidence indicates that AD is a pervasive metabolic disorder characterized and possibly caused by dysregulation of numerous biochemical pathways, which underlie its complex pathogenesis [ 146 , 147 ].…”

Section: Polyamine Pathway In Alzheimer’s Diseasementioning

confidence: 99%

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Polis

¹

,

Karasik

²

,

Samson

³

2021

Aging

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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.

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“…We demonstrated that norvaline upsurges the hippocampal levels of NOS1 [15] and NOS3 [16]; and therefore, increases the brain NO content. We speculate that the neuroprotective effects of norvaline are mainly mediated by NO generation and the reduction of oxidative stress, which is a principal characteristic of AD [99]. Moreover, NO has been shown to mediate neuronal differentiation of PC12 cells [100].…”

Section: Discussionmentioning

confidence: 91%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Srikanth

²

,

Gurevich

³

et al. 2020

IJMS

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Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

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“…We demonstrated that norvaline upsurges the hippocampal levels of NOS1 [15] and NOS3 [16]; and therefore increases the brain NO content. We speculate that the neuroprotective effects of norvaline are mainly mediated by NO generation and the reduction of oxidative stress, which is a principal characteristic of AD [79].…”

Section: Discussionmentioning

confidence: 96%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Gurevich

²

,

Bloch

³

et al. 2019

Preprint

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1

0

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Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer's disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis.Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administer an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and apply an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy.Remarkably, we evidence a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline shows no significant effect upon the progenitor cell number and constitution. We demonstrate that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identify a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.However, the existence of human adult neurogenesis has been a subject of intense scientific debate, until recently. Tobin et al. (2019) evidenced hippocampal neurogenesis persisting throughout life in the brains of centenarians and even of Alzheimer's disease (AD) patients [2]. Convincingly, they demonstrated that the density of NPCs, neuroblasts, and immature neurons significantly decreases in cases of mild cognitive impairment and in clinical AD as compared to healthy controls. In addition, various animal models of AD are characterized by diminished adult neurogenesis. In particular, triple-transgenic mice (3×Tg) show an age-dependent neurogenesis insufficiency that is detectable in the hippocampus starting at four months of age [3]. Of note, the decline of neurogenesis in this AD model precedes the manifestation of classical hallmarks of AD pathology, such as deposition of amyloid plaques and neurofibrillary tangles in the brain, as well as memory impairment. Remarkably, as a form of neuroplasticity, adult neurogenesis has been shown to modulate vulnerability to degenerative processes and influence the course of AD [4]. Moreover, various supporting adult neurogenesis treatment strategies have demonstrated their competence to counteract the pathological behavioral outcomes in murine AD models [5]. Nevertheless, the mechanisms that regulate NPC proliferation, ...

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A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Cited by 28 publications

References 130 publications

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

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