Resumen de New insights into alzheimer's disease: further characterization of the 3xtg-ad mouse model and a pharmacological approach with scfv-h3d6
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. The accumulation of the amyloid-β peptide (Aβ) is considered a key factor in its pathomechanism. The 3xTg-AD mouse model has become one of the most popular models of AD since it is described to progressively develop Aβ and tau pathologies by following a regional- and temporal-pattern analogous to human.
On the one hand, this thesis consists of the further understanding of AD by characterizing some traits of young (5-mo-old) 3xTg-AD mice by biochemical, histological, and behavioral assessing. Thus, in the central nervous system, intracellular Aβ pathology was detected in glutamatergic neurons at early stages of the disease. Interestingly, the extent of this pathology strongly correlated with neuron depletion, supporting the Aβ-mediated neurodegeneration. In the peripheral system, hepatic steatosis was observed, what could be related with alterations in the lipid metabolism, and enlarged red pulp from the spleen, supporting the erythrocyte-mediated clearance of Aβ. As well, behavioral and psychological-like symptoms and memory impairments were already exhibited at 5-mo-old. A longitudinal study from 5 to 9 months of age manifested the compensatory effect of the habituation and cognitive stimulation on the behavioral and cognitive deterioration.
On the other hand, targeting Aβ oligomers, which is the most cytotoxic species, is currently the main strategy in AD pharmacological research, specially by immunotherapy. Here, the effect of a single dose of the anti-Aβ single-chain variable fragment derived from bapineuzumab, scFv-h3D6, was tested in young 3xTg-AD mice. The treatment prevented neuron depletion and improved cognitive impairment by reducing Aβ pathology in terms of both the percentage of neurons involved and intracellular burden. Also, the white pulp from the spleen significantly grown with the treatment, suggesting the peripheral contribution of the macrophage-mediated elimination of the Aβ/scFv-h3D6 complex.
Furthermore, basic pharmacokinetic parameters of scFv-h3D6 were assessed and compared to an elongated version of the molecule, scFv-h3D6-EL. However, the improved thermodynamic stability and ability to rescue neuroblastoma cell-cultures from Aβ-induced toxicity displayed by scFv-h3D6-EL were not translated to mice. As well, intraperitoneal administered scFv-h3D6 was proven to be distributed as a compartmental model and, what is more interesting, to cross the blood-brain barrier. Once in the brain, this was internalized by both glial and neuron cells either as the isolated scFv or by forming Aβ/scFv-h3D6 complexes depending on the phase of the process.
In conclusion, this thesis provides some new insights in AD by the further characterization of the 3xTg-AD mouse model and by the characterization of the pharmacological approach with scFv-h3D6.
