Amyloid-b 1–42 (Ab42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer’s disease (AD) progression. Recent results suggested that Ab42 oligomers trigger activation of AMP- activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca2+]i induced by NMDA receptor activation or membrane depolar- ization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is suffi- cient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neu- rons against synaptotoxic effects of Ab42 oligomers in vitro and against the loss of dendritic spines observed in the human APPSWE,IND-expressing transgenic mouse model in vivo. AMPK phosphory- lates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Ab42 oligomers. Our results identify a CAMKK2-AMPK- Tau pathway as a critical mediator of the synapto- toxic effects of Ab42 oligomers.