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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221995
Addressing Alzheimer's disease through innovative mechanisms
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[eng] Alzheimer’s disease (AD) remains a major unmet medical need, with no effective disease- modifying treatments available despite decades of research and a growing socioeconomic burden associated with its increasing prevalence. This Thesis addresses AD by exploring innovative therapeutic strategies, including new combinations of biological targets as well as underexplored targets. Firstly, a new family of dual soluble epoxide hydrolase (sEH) and acetylcholinesterase inhibitors was developed. This target combination should lead to increased cognition and memory, as well as synergistic effects against the characteristic neuroinflammation of AD brains. A potent second-generation lead compound was identified, which overcame the metabolic and pharmacokinetic limitations of the first-generation lead and showed favourable physicochemical properties and in vitro pharmacokinetic and safety profile. Furthermore, it demonstrated efficacy in a mouse model of AD with enhancement of cognition and memory and reduction of several disease biomarkers, emerging as a promising drug candidate. Secondly, a novel family of small-molecule dual inhibitors of sEH and glutaminyl cyclase endowed with a high degree of structural diversity was developed, aiming to obtain disease-modifying effects by targeting neuroinflammation and beta-amyloid peptide pathologies, which are key hallmarks of AD pathological network. Its in vitro profiling led to the identification of a lead compound, which showed inhibitory activity in the nanomolar range for both targets, as well as good aqueous solubility, brain permeability, metabolic stability and an adequate safety profile. The selected compound also exhibited favourable biodistribution and safety profiles in mice, with demonstrated brain exposure and a relatively high maximum tolerated dose, as well as promising effects in a first proof of concept in a mouse model of AD (hQC x hAPP mice). The lead compound is currently undergoing additional in vivo efficacy studies in two different AD mouse models (5xFAD and SAMP8) with an adjusted dose aiming to prove its efficacy. Thirdly, the underexplored phosphatase domain of sEH, which has been related with cholesterol metabolism and might play a role in AD, has been also investigated, by the development of brain permeable compounds that selectively inhibit the phosphatase activity of the enzyme, without altering the hydrolase activity. Thus, the use of these novel compounds in additional studies will enable further exploration of the implication of this target in AD pathogenesis. Finally, the amyloidogenic Tar DNA-binding Protein 43 (TDP-43) has been addressed, due to its implication in over half of AD cases and considering the lack of drugs that directly target the protein, with two approaches: 1) a fast and unexpensive in vitro assay has been set up to facilitate the identification of TDP-43 aggregation inhibitors; 2) biophysical methods, namely surface plasmon resonance and differential scanning fluorimetry, have allowed the identification of a promising protein ligand, that will be used as the starting point for the design and optimisation of proteolysis targeting chimeras aiming to degrade TDP-43.
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MARTÍNEZ CONDE, Noemí. Addressing Alzheimer's disease through innovative mechanisms. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/221995]