Too much Aβ weakens neural synapses by favoring long-term depression, but how? A report published January 18 in Nature Neuroscience suggests that the peptide does so by hijacking the neuron’s own mechanisms of synaptic plasticity. Scientists led by José Esteban from the Spanish Research Council (CSIC), César Venero from the National Distance Education University in Madrid (UNED), and Shira Knafo of the University of the Basque Country find that Aβ helps recruit more than the usual amount of PTEN—a protein that previously has been implicated in long-term depression—to the postsynaptic membrane. This, they report, tips the balance away from long-term potentiation and toward depression. The findings give new insight into how Aβ might mess with cognition. “We knew that plasticity was out of balance in Alzheimer’s disease, but we didn’t know why,” Esteban told Alzforum. “This is one mechanism that explains how it is impaired.”
“The exact mechanism of Aβ-induced depression of synaptic transmission is still mysterious,” said Daniel Choquet of the Université de Bordeaux, France. This study “furthers our understanding of this phenomenon, and opens a new way to preventing Aβ-induced synaptic toxicity.” (See full comment below.)
PTEN—short for phosphatase and tensin homolog deleted on chromosome 10—is a lipid phosphatase best known for its role in tumor suppression throughout the body. The enzyme is also abundantly expressed in the adult brain. A decade ago it was first implicated in memory and synaptic long-term depression. LTD is a process that opposes long-term potentiation (LTP), preventing the latter from making synapses too strong (Wang et al., 2006).
A few years back, Esteban and colleagues picked up on these early reports. They observed that upon LTD, PTEN collects in the postsynaptic membrane, where it counteracts signaling of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) by dephosphorylating it to PIP2 (Jurado et al., 2010; Arendt et al., 2014). This reduces the activation of some downstream signaling molecules such as AKT, and activates others, such as GSK3BETA. Through further signaling steps that remain unclear, this removed AMPA receptors from the synapse and weakened the neuron’s response to glutamate (Arendt et al., 2010).
PTENs’ relocation to the postsynaptic membrane required it to bind to the scaffolding protein PSD-95, which anchors proteins to synapses via its 90-amino acid PDZ domain. PDZ domains are common to many proteins and are needed for protein-protein interactions (for a review, see Lee and Zheng, 2010).
In the present study, first author Knafo wondered if this process contributed to the pathological depression driven by Aβ. To find out, she infused either the PTEN inhibitor VO-OHpic or vehicle into the brain ventricles of four-month-old PS/APP mice or their wild-type littermates over three to four weeks. She then tested the animals’ spatial memories using novel-object-location and contextual-fear-conditioning tasks. While untreated PS-APP mice were impaired on both, treated transgenic mice explored a displaced object as long as wild types, and froze just as much in an environment where they had received foot shocks.
Experiments in hippocampal slices also supported the idea that PTEN was required for the depressive effects of Aβ. Whether slices were bathed in synthetic Aβ or in Aβ secreted by cultured neurons, both LTP and basal synaptic transmission dropped. In contrast, pre-incubating the slices with VO-OHpic protected them from these effects. PTEN and Aβ appeared to work in the same pathway, as LTD was enhanced in hippocampal slices from mice that overexpressed PTEN but synthetic Aβ oligomers increased it no further.
How might Aβ influence PTEN? The mechanism is unclear, but the researchers found that synthetic Aβ added to primary hippocampal neurons concentrated PTEN from dispersed locations into spine heads (see image above). This would be similar to the synapse-directed movement of PTEN the group previously reported in LTD. Like in the previous study, the scientists again report that this relocation depends on PTEN’s interaction with PDZ-binding domains, though it is unclear which specific proteins bind PTEN. Hippocampal slices from mice that produced PTEN lacking the last five amino acids of the PDZ-binding domain maintained normal LTP in spite of Aβ treatment. Together, the data suggest to the authors that Aβ somehow facilitates binding between PTEN and its PDZ-domain containing partners, which draws more of the protein to the synapse, causing more LTD than usual.
Might these findings translate into a therapeutic strategy? PTEN catalytic activity helps prevent cancer, hence blocking it would be dangerous, said Esteban. However, it may be safe to target only the protein’s binding of PDZ domains. Knafo and colleagues designed a peptide matching the last eight amino acids of the PDZ-binding region from rat and mouse PTEN. A pulldown assay revealed that it competed with PTEN for binding to PDZ-containing proteins. Incubated with hippocampal slices from mice, the peptide blocked LTD and warded off ill effects of synthetic Aβ on LTP. Infusing the peptide into the brains of PS/APP mice for three to four weeks rescued deficits in the novel-object-location and contextual-fear-conditioning tasks, the scientists report.
While this provides a preclinical proof of concept, peptides are large, unstable, and do not cross the blood-brain barrier, Esteban said. In an effort to find something suited to the clinic, his group is looking for a small molecule that interrupts PTEN-PDZ-interactions and can be given intravenously. The scientists are also trying to figure out how Aβ relocates PTEN.
This study is interesting and thorough, with clear experimental outcomes, wrote Gary Landreth, Case Western Reserve University, Cleveland, Ohio. However, he added, “The story, while provocative, remains incomplete so long as the PDZ-containing effector(s) that mediate the synaptic effects of the therapeutic peptide remain unknown.” (See full comment below.)—Gwyneth Dickey Zakaib
Research Models Citations
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