Editors' ChoiceNeuroscience

PTEN contributes to Alzheimer’s disease

Sci. Signal.  01 Mar 2016:
Vol. 9, Issue 417, pp. ec45
DOI: 10.1126/scisignal.aaf5520

The phosphatase PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)–AKT pathway by converting the phospholipid PIP3 to PIP2. PIP3-mediated PI3K-AKT signaling in neurons increases synaptic strength of active synapses, a phenomenon called long-term potentiation (LTP). Mutations in PTEN are associated with various neurological disorders, such as autism and seizures. In Alzheimer’s disease (AD), accumulation of the peptide β-amyloid (Aβ), produced from the product of the APP gene, is associated with depressed synaptic activity and neuronal cell death in the hippocampus and consequently cognitive dysfunction in the patient. Knafo et al. found that PTEN linked Aβ to postsynaptic depression (see also Frere and Slutsky). Transgenic whole-body overexpression of Pten in mice suppressed hippocampal synaptic activity, and adding Aβ to slices from these mice had no further depressive effect. PTEN inhibition with the drug VO-OHpic prevented Aβ-induced decreases in synaptic transmission and LTP in hippocampal slices and rescued cognitive function in a mouse model of AD. In hippocampal slices from a different mouse model, current through the glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type (AMPARs), but not glutamate receptors of the N-methyl-D-aspartate type (NMDARs), were reduced in neurons overexpressing App. Either PTEN inhibitors or overexpression of a dominant-negative PTEN mutant increased AMPAR currents in those neurons. However, PTEN inhibition had no effect on the amounts of amyloid precursor protein (APP) or Aβ in the mouse models tested. Together, these results suggested that PTEN may act downstream of Aβ in a common pathway to depress synaptic transmission.

To assess if PTEN was localized at synapses, the authors examined the distribution of fluorescent protein-tagged PTEN in hippocampal slices using time-lapse imaging, which showed that application of Aβ to hippocampal slices induced the redistribution of PTEN into the spines of neurons. Aβ also induced the accumulation of endogenous PTEN in synaptosomal lysates, confirming that the redistribution was not an overexpression artifact. This redistribution of PTEN was accompanied by a net decrease in phosphorylated AKT. PTEN contains a PDZ-binding domain that can anchor the phosphatase to the postsynaptic terminal. Indeed, Aβ-induced accumulation of PTEN was decreased in the spines of cultured neurons transfected with a truncated PTEN that lacked the PDZ motif. LTP and AMPAR synaptic transmission was unaffected by application of Aβ or overexpression of App in hippocampal slices taken from knock-in mice with PTEN that lacked part of the PDZ motif. A peptide designed to compete with PTEN for PDZ-domain binding prevented Aβ-induced synaptic depression in hippocampal slices and rescued cognitive deficits when infused into the brains of App/Psen1 mice. The findings suggest that blocking the recruitment of PTEN to synapses may reduce the onset and delay progression of neuronal and cognitive deficits in AD patients.

S. Knafo, C. Sánchez-Puelles, E. Palomer, I. Delgado, J. E. Draffin, J. Mingo, T. Wahle, K. Kaleka, L. Mou, I. Pereda-Perez, E. Klosi, E. B. Faber, H. M. Chapman, L. Lozano-Montes, A. Ortega-Molina, L. Ordóñez-Gutiérrez, F. Wandosell, J. Viña, C. G. Dotti, R. A. Hall, R. Pulido, N. Z. Gerges, A. M. Chan, M. R. Spaller, M. Serrano, C. Venero, J. A. Esteban, PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Nat. Neurosci. 19, 443–453 (2016). [PubMed]

S. Frere, I. Slutsky, Targeting PTEN interactions for Alzheimer’s disease. Nat. Neurosci. 19, 416–418 (2016). [PubMed]