Tyrosine phosphatase PTP1B impairs presynaptic NMDA receptor-mediated plasticity in a mouse model of Alzheimer's disease

Li Zhang; Zhaohong Qin; Fariba Sharmin; Wei Lin; Konrad M. Ricke; Michael A. Zasloff; Alexandre F.R. Stewart; Hsiao-Huei Chen

Neurobiology of Disease (Aug 2021)

Tyrosine phosphatase PTP1B impairs presynaptic NMDA receptor-mediated plasticity in a mouse model of Alzheimer's disease

Li Zhang,
Zhaohong Qin,
Fariba Sharmin,
Wei Lin,
Konrad M. Ricke,
Michael A. Zasloff,
Alexandre F.R. Stewart,
Hsiao-Huei Chen

Affiliations

Li Zhang: Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
Zhaohong Qin: Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
Fariba Sharmin: Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Wei Lin: Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
Konrad M. Ricke: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada
Michael A. Zasloff: Georgetown University School of Medicine, MedStar Georgetown Transplant Institute, Washington, DC, 2007, USA
Alexandre F.R. Stewart: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada; Correspondence to: A.F.R. Stewart, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada.
Hsiao-Huei Chen: Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Correspondence to: H.-H. Chen, 451 Smyth Road, Ottawa, Ontario K1H8M5, Canada.

Journal volume & issue: Vol. 156
p. 105402

Abstract

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Mutations in the beta-amyloid protein (APP) cause familial Alzheimer's disease. In hAPP-J20 mice expressing mutant APP, pharmacological inhibition or genetic ablation of the tyrosine phosphatase PTP1B prevents CA3 hippocampus neuron loss and cognitive decline. However, how targeting PTP1B affects the cellular mechanisms underlying these cognitive deficits remains unknown. Changes in synaptic strength at the hippocampus can affect information processing for learning and memory. While prior studies have focused on post-synaptic mechanisms to account for synaptic deficits in Alzheimer's disease models, presynaptic mechanisms may also be affected. Here, using whole cell patch-clamp recording, coefficient of variation (CV) analysis suggested a profound presynaptic deficit in long-term potentiation (LTP) of CA3:CA1 synapses in hAPP-J20 mice. While the membrane-impermeable ionotropic NMDA receptor (NMDAR) blocker norketamine in the post-synaptic recording electrode had no effect on LTP, additional bath application of the ionotropic NMDAR blockers MK801 could replicate the deficit in LTP in wild type mice. In contrast to LTP, the paired-pulse ratio and short-term facilitation (STF) were aberrantly increased in hAPP-J20 mice. These synaptic deficits in hAPP-J20 mice were associated with reduced phosphorylation of NMDAR GluN2B and the synaptic vesicle recycling protein NSF (N-ethylmaleimide sensitive factor). Phosphorylation of both proteins, together with synaptic plasticity and cognitive function, were restored by PTP1B ablation or inhibition by the PTP1B-selective inhibitor Trodusquemine. Taken together, our results indicate that PTP1B impairs presynaptic NMDAR-mediated synaptic plasticity required for spatial learning in a mouse model of Alzheimer's disease. Since Trodusquemine has undergone phase 1/2 clinical trials to treat obesity, it could be repurposed to treat Alzheimer's disease.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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