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Title
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Multimodal approach to unravel network disturbances and compensatory mechanisms during pre- and earlyplaque stages of Alzheimer’s Disease
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Author
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Abstract
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| Due to the aging world population, the number of people that are suffering from Alzheimer´s Disease (AD) is expected to dramatically increase. In AD, an accumulation of both toxic amyloid-beta (Aβ) aggregates and neurofibrillary tau tangles disrupts neuronal function, leading to severe cognitive deficits and behavioral alterations. AD is characterized by a long presymptomatic phase, where the progressive accumulation of Aβ and tau interferes with neuronal function. Early network imbalance during the presymptomatic phase, caused by synaptic dysfunction induced by soluble Aβ species, drives the progression of AD. Therefore, researchers hypothesize that restoration of the network imbalance at early stages of the disease could slow down or stop the disease progression of AD. In this thesis, we aimed to evaluate alterations in whole brain network activity and hippocampal oscillatory activity at pre- and early-plaque stages of AD and how this is linked to histopathological AD-related alterations and behavioral disturbances. For this purpose, we used a multimodal approach where we obtained results from resting state functional MRI, in vivo hippocampal measurements of neuronal activity in freely behaving animals, and ex vivo histological analysis. We investigated pre- and early-plaque stages of AD, using the TgF344-AD rat model displaying all phenotypical hallmarks of AD. We observed alterations in network activity during recurrent patterns of brain activity, so-called quasi-periodic patterns (QPP), at the pre-plaque stage of AD. Large differences in spatial activation occurred mainly in the basal forebrain (BFB) of TgF344-AD rats, which coincided with soluble Aβ pathology and astrogliosis in the BFB. During the early-plaque phase, spatial and temporal properties of QPPs in TgF344-AD rats were similar to the QPPs of wild-type littermates, and the astrogliosis in the BFB was diminished. Similarly, electrophysiology studies demonstrated during the pre-plaque stage of AD, alterations in neuronal activity within the hippocampus, a region important for learning and memory, which were partially recovered at the early-plaque stage in TgF344-AD rats. This partial recovery coincided with an increased number of hippocampal cholinergic synapses, suggesting that the cholinergic sprouting originating from the BFB might be an important compensatory mechanism during the early-plaque stage of AD. In summary, this thesis highlights the diagnostic potential of quasi-periodic pattern analysis as a noninvasive early biomarker for AD. In future studies, the assessment of quasi-periodic pattern analysis upon activation of cholinergic neurons in the BFB using chemogenetic tools could be a valuable strategy to gain insights into recovery of network activity in AD. |
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Language
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English
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Publication
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Antwerpen
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences
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2023
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Volume/pages
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XVII, 296 p.
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Note
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Verhoye, Marleen [Supervisor]
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Full text (open access)
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