ALPHA-SYNUCLEIN OLIGOMERS INDUCE MEMORY IMPAIRMENT INFLUENCED BY RAPID GLIAL CELL ACTIVATION

Abstract

Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly. Although the main neuropathological hallmarks of DLB and Parkinson's disease are intraneuronal inclusions made of alpha-synuclein (α-syn), evidence suggests also a neuropathogenic role for extracellular α-syn oligomers (α-synOs), nowadays considered as the more detrimental species. Increasing evidence suggests that these extracellular moieties activate glial cells leading to neuronal damage. Notably, resting state glial cells regulate synaptic activity guaranteeing the establishment of new memories, while their activation would preclude it. We ascertained if the memory impairment induced by α-synOs was associated with neuronal changes and dependent on glial cell activation and if Toll-like receptor 4 (TLR4), pivotal in the initiation of an immune response, was involved. ICV injections in C57 mice of α-synOs (1μM/7.5μL) was used to test the effect on memory by subsequent object recognition test (NORT) and long term potentiation (LTP) measure. The involvement of glial activation in the α-synO-mediated memory impairment was verified by the histological examination of astrocytes and microglia activation and the pre-treatment of mice with the anti-inflammatory drugs. The effect of α-synOs on memory and glial activation in TLR4 knockout mice (TLR4-/- mice) was also evaluated. A single injection of α-synOs abolished memory establishment and inhibit LTP in association to a short time activation of both microglial cells and astrocytes, without altering synaptic structure and neuronal organization in the hippocampus. Accordingly anti-inflammatory drugs prevented the memory impairment confirmed that glial activation is implicated in this α-synO detrimental action, but the involvement of TLR4 was ruled out since α-synO-mediated effects were still observable in TLR4-/- mice Our data demonstrate that α-synOs induced memory impairment involving activated glial cells through a TLR4-independent pathway. We provide evidence that an acute mouse model allows to specifically test α-synO mechanism of action and the efficacy of new therapeutic approaches aimed at counteracting their action.