Thus, increased levels of Aβ42, caused by chronic HF feeding and hyperglycemia or by excessive BACE1 cleavage of mutant APP, as in many familial AD cases and numerous AD rodent models (e.g., hAPPSw and hAPP23), will directly diminish NO bioavailability and indirectly elevate ET-1 levels. The gene discussed is APP; the disease is Hyperglycemia.