Unravelling the impacts of misfolded proteins in the initiation and progression of Alzheimer's disease

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder, eventually leading to dementia and affecting the elderly. Due to ageing of the population, the prevalence of AD is expected to rise, with a global cost of caretaking of AD patients estimated to hundreds of billion dollars. As the aetiology of AD pathology remains elusive, the development of appropriate curative therapies requires more in-depth knowledge on the early stages of AD pathology, which is the focus of this PhD. We studied the impacts of misfolded proteins encountered in AD (Aβ, tau) in the initiation and progression of AD pathology, using highly translational in vivo MRI techniques, in combination with the Tet-Off APP and hTau.P301L mouse models, simulating Aβ and tau pathology, respectively, in a context resembling sporadic AD. On the one hand, the Tet-Off APP mice showed early soluble Aβ-associated hyperconnectivity of brain networks prior to Aβ plaque formation, followed by a hypoconnectivity after the onset of Aβ plaque deposition which was associated with neuroinflammation surrounding the plaques. Furthermore, the effects of Aβ accumulation on the brain-wide glymphatic clearance were evaluated at a more advanced stage of AD and showed an impaired glymphatic brain fluid transport. More specifically, they demonstrated a reduced glymphatic inflow in the brain parenchyma affecting the dynamics of the glymphatic transport and thus presumably the effective clearance of brain waste, including Aβ. On the other hand, in the hTau.P301L mice, tau fibrils did not affect the functional connectivity of brain networks, despite progressive accumulation throughout the brain up to 15 weeks after seeding. In conclusion, the results presented in this thesis indicate that degradation of the brain’s functional integrity is associated with soluble Aβ toxicity, even in a context of sporadic AD. Moreover, Aβ toxicity seems to also impact the glymphatic brain fluid circulation directly and indirectly in AD pathology, with a brain-wide spread of neuroinflammatory responses. This demonstrates as well the importance of using neuroimaging techniques to shed light on the underlying mechanisms of the early events caused by the synergy between Aβ and tau, emphasizing the clinical relevance of preclinical studies using animal models, especially for the identification of new targets, as potential therapeutic strategies for AD.

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed