Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5-implications for dementia with Lewy bodies

Background: In dementia with Lewy bodies (DLB) abnormal interactions between alpha-synuclein (alpha-syn) and beta amyloid (A beta) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of A beta and alpha-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of alpha-syn and A beta in the hippocampus. Results: We generated double transgenic mice over-expressing amyloid precursor protein (APP) and alpha-syn under the mThy1 cassette and investigated the relationship between alpha-syn cleavage, A beta, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the alpha-syn/APP tg mice displayed greater accumulation of alpha-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and alpha-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the alpha-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater alpha-syn accumulation and neurodegeneration in the single and alpha-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with A beta oligomers and over-expressing alpha-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In alpha-syn-expressing neuronal cells lines, A beta oligomers promoted increased intracellular calcium levels, calpain activation and alpha-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of A beta in alpha-syn-expressing neuronal cells. Conclusions: Together, these results support the possibility that vulnerability of hippocampal neurons to alpha-syn and A beta might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB.