Chronic alpha-synuclein accumulation in rat hippocampus induces Lewy Bodies formation and specific cognitive impairments




11 May, 2020


Kasongo DW, de Leo G, Vicario N, Leanza G, Legname G


Occurrence of Lewy bodies/Lewy neurites (LBs/LNs) containing misfolded fibrillar alpha-synuclein (α-syn) is one of the pathological hallmarks of memory impairment-linked synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropathological substrates for cognitive symptoms are still elusive. Here, recombinant mouse α-syn fibrils were bilaterally injected in the hippocampus of female Sprague-Dawley rats, which underwent behavioral testing for sensory-motor and spatial learning and memory abilities. No sensory-motor deficits affecting Morris Water Maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months post-injection. These deficits were associated to a time-dependent increase in the levels of phosphorylated α-syn at serine 129 and in the stereologically estimated numbers of proteinase K-resistant α-syn aggregates within the hippocampus. Interestingly, pathological α-syn aggregates were found in the entorhinal cortex and, by 12 months post-injection, also in the vertical limb of the diagonal band and the piriform cortices. No pathological α-syn deposits were found within the Substantia Nigra, the Ventral Tegmental Area or the Striatum, nor was any loss of dopaminergic, noradrenergic or cholinergic neurons detected in α-syn injected animals, compared to controls. This would suggest that the behavioral impairments seen in the α-syn injected animals might be determined by the long-term α-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits.Significance Statement Cognitive deficits represent significant non-motor manifestation of Parkinson's disease and dementia with Lewy body, which deteriorates daily living activities leading to reduced independence, quality of life, and survival of affected patients. Therefore, the identification of anatomical and neuronal substrates underlying cognitive impairment can help in the development of appropriate treatments. Our data, confirm and extend previous observations showing that hippocampal alpha-synuclein pathology contribute to specific memory impairment. Thus, the alpha-synuclein pre-formed fibril infusion procedure in the rat may represent a feasible tool to model synucleinopathies with which to test possible therapeutic interventions.