APP palmitoylation is involved in the increase in Aβ1-42 induced by aluminum

Jing Song; Chunman Yuan; Wenjing Li; Ting Gao; Xiaoting Lu; Linping Wang

doi:10.1016/j.brainres.2021.147709

APP palmitoylation is involved in the increase in Aβ_1-42 induced by aluminum

Brain Res. 2022 Jan 1:1774:147709. doi: 10.1016/j.brainres.2021.147709. Epub 2021 Nov 7.

Authors

Jing Song¹, Chunman Yuan², Wenjing Li², Ting Gao², Xiaoting Lu³, Linping Wang³

Affiliations

¹ Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China; Key Lab of Cellular Physiology of Education Ministry, Shanxi Medical University, China. Electronic address: sj4933749@126.com.
² Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China.
³ Department of Occupational Health, School of Public Health, Shanxi Medical University, China; Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, China; Key Lab of Cellular Physiology of Education Ministry, Shanxi Medical University, China.

PMID: 34758347
DOI: 10.1016/j.brainres.2021.147709

Abstract

The increase in Aβ_1-42 is a neurotoxic effect induced by aluminum which can lead to impairment of learning and memory, but its mechanism has yet to be fully elucidated. Studies have shown that APP palmitoylation is appears to be involved in the production process of Aβ_1-42. Here, we investigated whether APP palmitoylation is related to the increase in Aβ caused by aluminum and its specific mechanism of action. In this study, APP palmitoylation was studied in the setting of aluminum-induced increases in Aβ_1-42 from two perspectives: whole animal experiments and in vitro cell experiments. First, the learning and memory of rats were impaired and the number of rat cortical neurons was decreased after staining with aluminum. Second, the expression of palmitoyl APP, APP in lipid rafts and palmitoyl acyltransferase zDHHC7 both in rat cerebral cortex and PC12 cells increased with the production of Aβ_1-42 induced by aluminum in a dose-dependent manner. Finally, the intervention with the palmitoylation inhibitors 2-BP and siRNA zDHHC7 in PC12 cells reduced levels of palmitoyl APP, the expression of APP in lipid rafts and the content of Aβ_1-42 induced by aluminum to a certain extent. Our results indicate that increased APP palmitoylation levels may be related to the increase in Aβ_1-42 caused by aluminum, and the mechanism may involve APP palmitoylation promoting the accumulation of APP protein on lipid rafts and the cleavage of APP by BACE1 in amyloidogenic pathway. The increase in expression of zDHHC7 may be one of the reasons for the increase in levels of APP palmitoylation caused by aluminum.

Keywords: APP; Aluminum; Aβ; Palmitoylation; zDHHC7.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyltransferases / metabolism
Aluminum / pharmacology*
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / metabolism*
Animals
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Learning / drug effects
Lipoylation / drug effects
Membrane Microdomains / drug effects
Membrane Microdomains / metabolism
Memory / drug effects
Neurons / drug effects*
Neurons / metabolism
PC12 Cells
Peptide Fragments / metabolism*
Rats

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Peptide Fragments
amyloid beta-protein (1-42)
Aluminum
Acetyltransferases