Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and potentially, Alzheimer’s disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer’s disease cytosol, accompanied by downstream loss of the spine actin-regulatory protein drebrin. Beta-Amyloid (A) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer’s disease brain and in 22-month-old Tg2576 transgenic Alzheimer’s disease mice. This active PAK co-immunoprecipitated with the small GTPase Rac and both translocated to granules. A42 oligomer treatment of cultured hippocampal neurons, induced similar effects, accompanied by reduction of dendrites that was protected by kinase\-active but not kinase-dead PAK. A42 oligomer treatment also significantly reduced NMDA receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation, but not the loss of p-NR2B in Aß42 oligomer-treated neurons. Src family kinases are known to phosphorylate the rac activator Tiam1 which has recently been shown to be Aß-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic Alzheimer’s disease mice and in A42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in A42 oligomer-induced signaling and synaptic deficits in Alzheimer’s disease.