High temperature promotes amyloid ß-protein production and γ-secretase complex formation via Hsp90.
J Biol Chem
; 295(52): 18010-18022, 2020 12 25.
Article
em En
| MEDLINE
| ID: mdl-33067321
ABSTRACT
Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of ß-amyloid-protein (Aß) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25-40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aß production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aß production. Here, we report temperature-dependent regulation of Aß production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aß production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39⯰C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aß production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30⯰C) compared with those housed at standard room temperature (23⯰C). Our results suggest that high temperature regulates Aß production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.
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MEDLINE
Assunto principal:
Membrana Celular
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Peptídeos beta-Amiloides
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Precursor de Proteína beta-Amiloide
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Proteínas de Choque Térmico HSP90
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Secretases da Proteína Precursora do Amiloide
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Temperatura Alta
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article