Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons

One major pathological hallmark of Alzheimer's disease (AD) is the accumulation of senile plaques mainly composed of neurotoxic amyloid beta-peptide (A beta) in the patients' brains. Sonic hedgehog (SHH) is a morphogen critically involved in the embryonic development of the central nervous system (CNS). In the present study, we tested whether A beta may induce SHH expression and explored its underlying mechanisms. We found that both A beta 25-35 and A beta 1-42 enhanced SHH expression in the primary cortical neurons derived from fetal rat brains. Immunohistochemistry revealed heightened expression of SHH in the cortex and hippocampus of aged (9 and 12 months old) AD transgenic mouse brains as compared to age-matched littermate controls. Chromatin immunoprecipitation (ChIP) assay demonstrated that A beta 25-35 enhanced binding of hypoxia-inducible factor-1 (HIF-1) to the promoter of the Shh gene in primary cortical cultures; consistently, A beta 25-35 induction of SHH was abolished by HIF-1 alpha small interfering RNA (siRNA). A beta 25-35 also time-dependently induced inhibitor of differentiation-1 (Id1) that has been shown to stabilize HIF-1 alpha; further, A beta 25-35-mediated induction of HIF-1 alpha and SHH was both suppressed by Id1 siRNA. Pharmacological induction of HIF-1 alpha by cobalt chloride and application of the cell-permeable recombinant Id1 proteins were both sufficient to induce SHH expression. Finally, both the SHH pathway inhibitor cyclopamine and its neutralizing antibody attenuated A beta cytotoxicity, albeit to a minor extent. These results thus established a signaling cascade of A beta -> aEuro parts per thousand Id1 -> aEuro parts per thousand HIF-1 -> aEuro parts per thousand SHH in primary rat cortical cultures; furthermore, SHH may in part contribute to A beta neurotoxicity.