Neurobiology of Disease Energy Inhibition Elevates -Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer’s Disease Pathogenesis

-Secretase [-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the -amyloid (A) peptide involved in the pathogenesis of Alzheimer’s disease (AD). BACE1 levels and activity are increased in AD brain andare likely todriveAoverproduction, but the causeofBACE1elevation inAD isunknown. Interestingly, cerebral glucosemetabolism and blood flow are both reduced in preclinical AD, suggesting that impaired energy production may be an early pathologic event in AD. To determine whether reduced energy metabolism would cause BACE1 elevation, we used pharmacological agents (insulin, 2-deoxyglucose, 3-nitropropionic acid, and kainic acid) to induce acute energy inhibition in C57/B6 wild-type and amyloid precursor protein (APP) transgenic (Tg2576) mice. Four hours after treatment, we observed that reduced energy production caused a 150% increase of cerebral BACE1 levels comparedwith control. Although this was amodest increase, the effect was long-lasting, because levels of theBACE1 enzyme remained elevated for at least 7 d after a single dose of energy inhibitor. InTg2576mice, levels of theBACE1-cleaved APP ectodomain APPs were also elevated and paralleled the BACE1 increase in both relative amount and duration. Importantly, cerebral A40 levels in Tg2576 were increased to 200 % of control at 7 d after injection, demonstrating that energy inhibition was potentially amyloidogenic. These results support thehypothesis that impaired energyproduction in thebrainmaydriveADpathogenesis by elevating BACE1 levels and activity, which, in turn, lead to A overproduction. This process may represent one of the earliest pathogenic events in AD. Key words: Alzheimer’s disease pathogenesis; -secretase; BACE1; -amyloid peptide; APP transgenic mice; energy metabolis