Calcium (Ca2+)-dependent neuroplasticity is critical for normal brain function and cognition. Dysregulation of Ca2+ signaling causes neuronal cell death by excitotoxic stress. One pathway that responds to changes in intracellular Ca2+ levels is mediated through Ca2+/calmodulin-dependant kinase kinase-2 (CaMKK2). In neuronal cells, CaMKK2 acts as pathway hub to activate downstream kinases including CaMKI, CaMKIV, AKT and AMP-activated protein kinase (AMPK). AMPK in turn phosphorylates Tau protein, implicating CaMKK2/AMPK signaling as very relevant to Alzheimer's Disease (AD). CaMKK2-dependent activation of AMPK is necessary and sufficient to cause amyloid β (Aβ)-dependent Tau hyperphosphorylation in neuronal cell culture and rodent models of AD. These results define a model of AD where CaMKK2 hyperactivity drives the detrimental consequences of Aβ accumulation. We will test if pharmacological inhibition of CaMKK2 can ameliorate the deficits caused by failed Ca2+ homeostasis leading to Tau hyperphosphorylation.