Alpha-synuclein oligomers acutely induce memory deficits and brain inflammation

Abstract

Lewy body dementia (LBD) is an alpha-synucleopathy which is considered as the second most common form of dementia characterized by cognitive dysfunctions, which occur also in patients with Parkinson's disease (PD). Neuropathological hallmarks of LBD and PD are represented by neuronal inclusions composed of alpha-synuclein (α-syn) which is considered as a pathogenetic factor. Emerging evidence suggests that extracellular α-syn oligomers (α-synO) might be central pathological species. Our main objectives were ascertain: 1. the effect of extracellular α-synO on synaptic plasticity and memory; 2. glial cell activation which regulate synaptic plasticity and memory formation; 3. the involvement of the toll-like receptor 4 (TLR4). To test α-synO effect on memory, they were ICV injected in C57 mice (1μM/7.5μL) subsequently tested in the novel object recognition test (NORT). Long term potentiation (LTP) was also measured. The involvement of neuroinflammation was investigated through 1. NORT measuring the ability of an anti-inflammatory drug to prevent α-synO-mediated memory deficit; 2. TLR4 knock-out mice and 3. immunohistochemistry for glial cell activation following α-synO injection. α-synO significantly impaired memory and LTP. In addition we found that a single injection of α-synO induced neuroinflammation. α-synO-mediated neuroinflammation contributed to the memory impairment, since it was prevented by the treatment with an anti-inflammatory drug. We also found that the TLR4 pathway was not involved in mediating the cognitive impairment since α-synO affected memory also in mice lacking the TLR4. Our data provide a new acute mouse model to test the efficacy of new therapeutic approaches directed toward α-synO and to study their mechanism of action at multiple levels.