Hippocampal CysLT1R overexpression or activation accelerates memory deficits, synaptic dysfunction, and amyloidogenesis in young APP/PS1 transgenic mice
ANNALS OF TRANSLATIONAL MEDICINE(2021)
Abstract
Background: Our previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLT(1)R) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer's disease (AD); however, whether CysLT(1)R upregulation has deleterious effects on AD remains elusive. Methods: In this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLT1R overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLT1R), into the bilateral dentate gyri (DG) of the hippocampus or CysLT(1)R activation by repeated systemic administration of its agonist YM-17690 (0.1 mg/kg, once a day, i.p., for 28 d). Results: The behavior data showed that overexpression of CysLT1R in hippocampal DG or administration of YM-17690 deteriorated behavioral performance in Morris water maze (MWM), Y-maze tests, and novel object recognition (NOR) in young APP/PS1 mice. The further studies showed that these treatments significantly destroyed synaptic function, as evidenced by impaired hippocampal long-term potentiation (LTP), decreased spine density, low number of synapses, and decreased postsynaptic protein (PSD95), and promoted the generation of amyloid beta (A beta) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice. Conclusions: Together, our results indicate that CysLT1R upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus.
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Key words
Cysteinyl leukotrienes receptor 1,Alzheimer's disease (AD),memory,synaptic plasticity,amyloidogenesis
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