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Investigating the mechanistic convergence between arterial stiffness and Alzheimer’s disease

Book - Dissertation

The unprecedented rise in the world’s elderly population will increase the prevalence of cardiovascular and neurodegenerative disorders. Recently, there has been an increased interest in the potential interplay between arterial stiffness (AS), an independent risk factor for cardiovascular disease and Alzheimer’s disease (AD). Although overwhelming evidence highlights the association between both diseases in human subjects, these studies are limited by associative evidence. In this thesis, we used several mouse models to investigate the mechanistic convergence between AS and AD. First, we performed a neurobehavioral evaluation of aging C57BL/6J mice, a commonly used background strain for AD mouse models, and concluded age-related memory loss in C57BL/6J animals. We then investigated the effect of endothelial nitric oxide synthase (NOS) knockout or pharmacological non-selective NOS inhibition. We concluded that only pharmacological, non-selective NOS inhibition induces cardiac dysfunction, AS, and a decrease in hippocampal-dependent learning and memory. Further LC-MS/MS proteomics analyses of hippocampal tissue of these treated C57BL/6J mice implicated molecular signatures of GABAergic signaling dysfunction and tauopathy. The same pharmacological intervention in an AD mouse model (hAPP23+/-) showed the induction of AS and a decrease in hippocampal-dependent learning and memory. Because AS and AD are age-related disorders, a longitudinal experiment was included, studying a novel in-house bred hybrid mouse model of AS and AD. From a (cardio)vascular perspective, we found a corticosterone-dependent effect on in vivo AS measurements, and hypertension resulting in long-term increased cardiac load. Neurologically, we concluded an impaired short-term episodic learning and memory from an early age and an increased cerebral amyloid load, tauopathy and cerebrovascular leakage later in life. Subsequently, we induced AS and hypertension pharmacologically in two different AD models (hAPP23+/− and hAPPswe/PSEN1dE9 mice) and concluded that learning and memory and cerebral amyloid load were not affected. An in-depth investigation of (cardio)vascular functionality in hAPP23+/− animals demonstrated altered stress hormone levels and altered in vivo vascular function, where ex vivo AS remained unchanged. There is increasing evidence of a link between metabolic and dementia syndromes. We further investigated the association between the metabolic syndrome and AD and showed the pre-symptomatic presence of peripheral insulin resistance in young hAPP23+/- mice, which eventually evolved into hyperinsulinemia in a symptomatic AD phase. Taken together, we identify four pre-symptomatic AD biomarkers, namely in vivo AS, cortisol, insulin resistance, and nitric oxide, which contribute to a better understanding of the mechanistic convergence between AS and AD.
Number of pages: 303
Publication year:2022
Keywords:Doctoral thesis
Accessibility:Closed