Long-Term Acetylcholinesterase Depletion Alters the Levels of Key Synaptic Proteins while Maintaining Neuronal Markers in the Aging Zebrafish (Danio rerio) Brain

Gerontology. 2023;69(12):1424-1436. doi: 10.1159/000534343. Epub 2023 Oct 4.

Abstract

Introduction: Interventions targeting cholinergic neurotransmission like acetylcholinesterase (AChE) inhibition distinguish potential mechanisms to delay age-related impairments and attenuate deficits related to neurodegenerative diseases. However, the chronic effects of these interventions are not well described.

Methods: In the current study, global levels of cholinergic, cellular, synaptic, and inflammation-mediating proteins were assessed within the context of aging and chronic reduction of AChE activity. Long-term depletion of AChE activity was induced by using a mutant zebrafish line, and they were compared with the wildtype group at young and old ages.

Results: Results demonstrated that AChE activity was lower in both young and old mutants, and this decrease coincided with a reduction in ACh content. Additionally, an overall age-related reduction in AChE activity and the AChE/ACh ratio was observed, and this decline was more prominent in wildtype groups. The levels of an immature neuronal marker were upregulated in mutants, while a glial marker showed an overall reduction. Mutants had preserved levels of inhibitory and presynaptic elements with aging, whereas glutamate receptor subunit levels declined.

Conclusion: Long-term AChE activity depletion induces synaptic and cellular alterations. These data provide further insights into molecular targets and adaptive responses following the long-term reduction of AChE activity that was also targeted pharmacologically to treat neurodegenerative diseases in human subjects.

Keywords: Acetylcholinesterase; Aging; Cholinergic system; Neuronal changes; Synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase* / metabolism
  • Aging
  • Animals
  • Brain / metabolism
  • Cholinergic Agents / metabolism
  • Humans
  • Neurodegenerative Diseases*
  • Zebrafish / metabolism

Substances

  • Acetylcholinesterase
  • Cholinergic Agents

Grants and funding

This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK, Grant No. 215S701) to Hulusi Kafaligonul and an EMBO Installation Grant (funds provided by TUBITAK) to Michelle M. Adams. The authors ETK-E, MUT-S, and AK were supported by the TUBITAK 2211-A/E National Graduate Scholarship Programme (BIDEB).