The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease

Tong Zhang; Minh D A Luu; Amalia M Dolga; Ulrich L M Eisel; Martina Schmidt

doi:10.3389/fphys.2023.1207280

The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease

Front Physiol. 2023 Jun 19:14:1207280. doi: 10.3389/fphys.2023.1207280. eCollection 2023.

Authors

Tong Zhang^{1

2}, Minh D A Luu¹, Amalia M Dolga¹, Ulrich L M Eisel², Martina Schmidt^{1

3}

Affiliations

¹ Department of Molecular Pharmacology, University of Groningen, Groningen, Netherlands.
² Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands.
³ Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

Keywords: Alzheimer’s disease; Parkinson disease; cAMP; ferroptosis; mitochondria; oxidative stress; parthanatos.

Publication types

Review

Grants and funding

AD is the recipient of an Alzheimer Nederland grant (WE.03-2018-04, Netherlands), Parkinson Fonds (Netherlands) and a Rosalind Franklin Fellowship co-funded by the European Union and the University of Groningen. UE and MS received support by Alzheimer Nederland grant WE.03-2019-05. MS was supported by the Deutsche Forschungsgemeinschaft (IRTG1874DIAMICOM-SP2) and Novartis unrestricted grant 50199468.