Transcriptional Regulation Of Secretase Genes In Alzheimer's Disease

Deposition of beta-amyloid peptide (Aβ) in the brain is the one of the mostcritical pathological hallmarks in Alzheimer's disease (AD).Aβis generated bysequential proteolytic cleavages of beta-amyloid precursor protein (APP) by twosecretases,β-secretase (BACE 1) andγ-secretase.However,knowledge ontranscriptional regulation of these secretase genes is limited.The incidence of AD isgreatly increased following cerebral ischemia and stroke in which hypoxic conditionsoccur in affected brain areas.However,a direct molecular link between hypoxicinsults and APP processing has yet to be established.Here,we demonstrate that acutehypoxia increases the expression and the enzymatic activity of BACE1 byup-regulating the level of BACE1 mRNA,resulting in increases in the APPC-terminal fragment-β(βCTF) and Aβ.Sequence analysis,mutagenesis,and gel shiftstudies revealed binding of HIF-1 (hypoxia-inducible factor 1) to the BACE1promoter.Overexpression of HIF-1αincreases BACE1 mRNA and protein level,whereas down-regulation of HIF-1αreduced the level of BACE 1.Hypoxic treatmentfails to further potentiate the stimulatory effect of HIF-1αoverexpression on BACE 1expression,suggesting that hypoxic induction of BACE 1 expression is primarilymediated by HIF-1α.Finally,we observed significant reduction in BACE 1 proteinlevels in the hippocampus and the cortex of HIF-1αconditional knock-out mice.Ourresults demonstrate that the expression of mouse BACE 1 is transcriptionally regulatedby HIF-1 and provide a molecular mechanism for increased incidence of ADfollowing cerebral ischemic and stroke injuries.Furthermore,we characterizedupstream regions of the human nicastrin gene and identified sequences critical fortheir promoter activity.Sequence analysis of this region revealed several potentialtranscription factor binding sites,which are confirmed by site mutations and gel shiftassays.Together our results further elucidated transcriptional regulation of BACE 1and theγ-secretase component nicastrin,providing invaluable information for futureAD therapeutics for reducing Aβgeneration by inhibiting secretase activities at thetranscriptional level.