Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment.
Ecotoxicol Environ Saf
; 220: 112365, 2021 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-34058678
ABSTRACT
Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0-100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0-800 µM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 µM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of ß-secretase, Aß40, and Aß42 or the activity of ß-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Precursor de Proteína beta-Amiloide
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Secretasas de la Proteína Precursora del Amiloide
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Disfunción Cognitiva
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Manganeso
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Ecotoxicol Environ Saf
Año:
2021
Tipo del documento:
Article