PTEN Mediates Alzheimer's Synaptic and Cognitive Failure

Knafo, S. 1, 2, 3

1 The Basque Country University
2 Biophysics Unit
3 IkerBasque, Basque Foundation for Science

Dyshomeostasis of amyloid-ß peptide (Aß) is responsible for synaptic malfunctionsleading to a range of cognitive deficits from mild impairment to full-blown dementia in Alzheimer's disease.Aß appears to skew synaptic plasticity events towards depression. We show that inhibition of PTEN, a lipid phosphatase essential to long-term depression,rescues normalsynaptic function and cognition incellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpress PTEN display synaptic depression that mimics and occludes Aß-induced depression. Mechanistically, Aß triggers a PDZ-dependent recruitment of PTEN into the post-synaptic compartment. Using a PTEN knock-in mouse lacking PTEN-PDZ interactions, we demonstrate that this mechanism is crucial for Aß's synaptic toxicity. Finally, we developed a pharmacological tool from the PDZ motif of PTEN that protectsneurons against Aß. These results provide fundamental information on the molecular mechanisms of Aß-induced synaptic malfunction, and may offer new mechanism-based therapeutic approaches to counteract downstream Aß signaling.