High temperature promotes amyloid β-protein production and γ-secretase complex formation via Hsp90.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of b-amyloid-protein (Ab) 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 Ab production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Ab production. Here, we report temperature-dependent regulation ofAb production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Ab production in amyloid precursor proteinoverexpressing 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 g-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature g-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 Ab production and the increased formation of the g-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 g-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard roomtemperature (23 °C). Our results suggest that high temperature regulates Ab production by modulating g-secretase complex formation through the binding of Hsp90 to NCT/APH-1. [ABSTRACT FROM AUTHOR]