Review Volume 13, Issue 7 pp 10770—10795

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Baruh Polis1, , David Karasik2,3, , Abraham O. Samson1, ,

  • 1 Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
  • 2 Hebrew SeniorLife, Hinda and Arthur Marcus Institute for Aging Research, Boston, MA 02131, USA
  • 3 Musculoskeletal Genetics Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel

Received: February 26, 2021       Accepted: March 27, 2021       Published: April 3, 2021
How to Cite

Copyright: © 2021 Polis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


ROS: reactive oxygen species; PSR: polyamine stress response; AD: Alzheimer’s disease; LUCA: last universal common ancestor; UPR: unfolded protein response; ER: endoplasmic reticulum; ODC: ornithine decarboxylase; ADC: arginine decarboxylase; AGM: agmatinase; CNS: central nervous system; H2O2: hydrogen peroxide; Arg: arginase; OTC: ornithine transcarbamylase; CPS1: carbamoyl phosphate synthetase 1; LPS: lipopolysaccharide; TNFα: tumor necrosis factor alpha; LDL: low-density lipoprotein; MMP: mitochondrial membrane potential; ODC-AZ ODC: antizyme; SSAT: spermidine/spermine acetyltransferase; PAO: polyamine oxidase; SMO: spermine oxidase; DNA: deoxyribonucleic acid; RNA: ribonucleic acid; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; nAChR: nicotinic acetylcholine receptors; NMDA: N-methyl-D-aspartate; DFMO: difluoromethylornithine; mTOR: mechanistic target of rapamycin; S6K1: ribosomal protein S6 kinase beta-1; HDAC: histone deacetylase; KO: knockout.