Key Mechanism Which Prevents Memory Loss in Alzheimer’s Disease Discovered

Neurons communicate with one another by synaptic connections, where information is exchanged from one neuron to its neighbor. These connections are not static, but are continuously modulated in response to the ongoing activity (or experience) of the neuron. This process, known as synaptic plasticity, is a fundamental mechanism for learning and memory in humans as in all animals. In fact, we now know that alterations in synaptic plasticity are responsible for memory impairment in cognitive disorders such as Alzheimer’s disease. Nevertheless, the mechanisms by which these alterations take place are still starting to be uncovered.

A new paper, published in Nature Neuroscience, reports that in Alzheimer’s disease, synaptic plasticity is altered by a protein originally described as a tumor suppressor: PTEN. In 2010, the research group of Dr. Esteban discovered that PTEN is recruited to synapses during normal (physiological) synaptic plasticity. This new investigation by Drs. Knafo, Venero and Esteban, now indicates that this mechanism runs uncontrolled during Alzheimer’s disease. One of the pathological agents of the disease, the beta-amyloid, drives PTEN into synapses excessively, unbalancing the mechanisms for synaptic plasticity and impairing memory formation.

An important aspect of this study is that it also describes how PTEN is recruited to synapses in response to beta-amyloid, and proposes a strategy to prevent it from occuring. Using a mouse model of Alzheimer’s disease, the investigators developed a molecular tool to shield synapses from the recruitment of PTEN. With this tool, neurons are rendered resistant to beta-amyloid, and Alzheimer’s mice preserve their memory.

Diagram of neurons and synapses.
Using a mouse model of Alzheimer’s disease, the investigators developed a molecular tool to shield synapses from the recruitment of PTEN. With this tool, neurons are rendered resistant to beta-amyloid, and Alzheimer’s mice preserve their memory. Image is for illustrative purposes only.

Although this is basic research using animal models, these studies contribute to dissect the mechanisms that control our cognitive function, and orient us towards potential therapeutic avenues for mental diseases where these mechanisms are deficient.

About this Alzheimer’s research

Source: Matxalen Sotillo – University of the Basque Country
Image Source: The image is in the public domain
Original Research: Abstract for “PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models” by Shira Knafo, Cristina Sánchez-Puelles, Ernest Palomer, Igotz Delgado, Jonathan E Draffin, Janire Mingo, Tina Wahle, Kanwardeep Kaleka, Liping Mou, Inmaculada Pereda-Perez, Edvin Klosi, Erik B Faber, Heidi M Chapman, Laura Lozano-Montes, Ana Ortega-Molina, Lara Ordóñez-Gutiérrez, Francisco Wandosell, Jose Viña, Carlos G Dotti, Randy A Hall, Rafael Pulido, Nashaat Z Gerges, Andrew M Chan, Mark R Spaller, Manuel Serrano, César Venero and José A Esteban in Nature Neuroscience. Published online January 18 2016 doi:10.1038/nn.4225


Abstract

PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer’s disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer’s disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

“PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models” by Shira Knafo, Cristina Sánchez-Puelles, Ernest Palomer, Igotz Delgado, Jonathan E Draffin, Janire Mingo, Tina Wahle, Kanwardeep Kaleka, Liping Mou, Inmaculada Pereda-Perez, Edvin Klosi, Erik B Faber, Heidi M Chapman, Laura Lozano-Montes, Ana Ortega-Molina, Lara Ordóñez-Gutiérrez, Francisco Wandosell, Jose Viña, Carlos G Dotti, Randy A Hall, Rafael Pulido, Nashaat Z Gerges, Andrew M Chan, Mark R Spaller, Manuel Serrano, César Venero and José A Esteban in Nature Neuroscience. Published online January 18 2016 doi:10.1038/nn.4225

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