Neurodegenerative diseases (NDs) include a broad range of age-related neuropathological conditions characterized by a slow but unstoppable highly selective degenerative process. It involves distinct subsets of neurons in specific anatomic systems leading to variable disease phenotypes such as cognitive impairment, movement disorders or a combination of both. However, the gradual accumulation of misfolded protein aggregates in well-ordered structures, habitually called amyloid represent a common feature of NDs and is thought to be at the root of these diseases. some of these proteins are prion protein, beta amyloid, tau, TDP43 and alpha synuclein on which we focused our attention. Alpha-synuclein(α-syn) is a 140 amino acid protein widely expressed in the brain occurring as a soluble or membrane-associated protein at presynaptic nerve terminals. It is mainly involved in synaptic vesicle release and trafficking. In its membrane-bound protein form, α-syn has a predominantly α-helical structure which under certain conditions can alternatively fold into a β-sheet-rich structure that easily polymerizes into amyloid fibrils and aggregates. These aggregates acquire neurotoxicity affecting mitochondrial function, endoplasmic reticulum–Golgi trafficking, protein degradation and/or synaptic transmission, leading to neurodegeneration. Interestingly, aggregated forms of α-syn can recruit and seed the endogenous protein and initiate the spreading throughout cells, thus suggesting a prion-like mechanism. The occurrence of Lewy bodies/Lewy neurites containing misfolded fibrillar α-syn constitutes one of the pathological hallmarks of synucleinopathies such as Parkinson’s disease, dementia with Lewy Bodies and multiple system atrophy, all linked to memory impairments. While it has been shown that brainstem Lewy bodies may contribute to motor symptoms, the anatomical and neuropathological substrates for cognitive symptoms are still elusive. Therefore, in this PhD thesis I sought to investigate the progressive pathologic alterations and spreading of synthetic α-syn fibrils bilaterally injected into the hippocampus of adult female Sprague-Dawley rats, up to the onset of memory impairments. Animals underwent behavioral testing for sensory-motor and spatial learning and memory abilities at different time-points post-injection. At no time-point was any sensory-motor deficits observed that could affect performance in the Morris Water Maze task, nor was any reference memory disturbances detected in any of the 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, all anatomically related to the injected sites. No pathological α-syn deposits were found within the Substantia Nigra, the Ventral Tegmental Area or the Striatum, nor was any obvious 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 persisting α-syn neuropathology in the affected neurons rather than by neurodegeneration per se. This study confirms and extends previous observations showing that hippocampal α-syn pathology contribute to specific memory impairment. In addition, the α-syn preformed fibrils infusion procedure in the rat may represent a feasible tool to model synucleinopathies with which to test possible therapeutic interventions.
FUNCTIONAL CONSEQUENCES OF AGGREGATED ALPHA-SYNUCLEIN HIPPOCAMPAL ACCUMULATION IN RATS / Kasongo, Walu Emakana Danielle. - (2021 Jul 29).
|Autori:||Kasongo, Walu Emakana Danielle|
|Titolo:||FUNCTIONAL CONSEQUENCES OF AGGREGATED ALPHA-SYNUCLEIN HIPPOCAMPAL ACCUMULATION IN RATS|
|Relatore/i esterni:||Leanza, Giampiero|
|Data di pubblicazione:||29-lug-2021|
|Appare nelle tipologie:||8.1 PhD thesis|