Hippocampal CysLT1R overexpression or activation accelerates memory deficits, synaptic dysfunction, and amyloidogenesis in young APP/PS1 transgenic mice.

Background: Our previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLTR) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer's disease (AD); however, whether CysLTR upregulation has deleterious effects on AD remains elusive.

Methods: In this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLTR overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLTR), into the bilateral dentate gyri (DG) of the hippocampus or CysLTR 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 CysLTR 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 β (Aβ) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice.

Conclusions: Together, our results indicate that CysLTR upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus.