Lopera Restrepo, Francisco Javier2020-10-272020-12-172020-10-272020-12-172009https://colciencias.metadirectorio.org/handle/11146/39183Among neurodegenerative diseases leading to dementia, Alzheimer's disease (AD) is the most common affecting 50-60% of dementia patients. Less than 20% of AD cases are of genetic origin whether causative or as a risk factor. Definite diagnostic is performed post mortem in brain tissue showing the histopathological hallmarks of the disease, amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular accumulation of several proteins and cellular subproducts. However, the main component is the beta amyloid peptide (A-beta) which is a cleavage product of the Amyloid precursor protein (APP). All known genes for familial AD involve APP metabolism and production of beta amyloid peptide. Neurofibrillary tangles (NFT) are intracellular aggregates of hyperphosphorylated Tau (pTau) protein, one of the microtubule associated proteins. Therefore, protein aggregation is one of the major events in AD. Despite these common hallmarks for familial and sporadic AD there is some evidence that points to differential aggregation patterns between familial and sporadic forms. Even within one causative gene mutations for AD such as Presenilin 1 (PS1) there is wide variability in clinical and neuropathological phenotypes. Protein turnover is one of the cellular homeostasis mechanisms; its goal is to maintain balance between protein production and degradation. Under cellular stress there are some attempts to preserve this balance, first by controlling Endoplasmic Reticulum (ER) protein production and releasing, an event known as unfolded protein response (UPR). It this mechanism fails then several protein degradation pathways are activated such as the ubiquitin-proteasome pathway or the lysosome-autophagy pathway. Failure in the UPR or protein degradation pathways will lead to cellular death. Neurons are specialized cells with structural and metabolic characteristics that render them susceptible to homeostasis imbalance; therefore protein aggregation is particularly deleterious for neurons. Several neurodegenerative diseases, including AD are characterized by protein aggregates and eventually neuronal death. Other indicators of cellular stress include activation of selected kinases pathways and mitochondrial dysfunction. These processes are important for cellular fate definition and could lead to apoptosis. Both of them have been identified as key players in neurodegeneration, particularly in AD. We propose that alongside with differential aggregation patterns of A-beta peptide and pTau there are some differences between familial and sporadic forms of AD regarding cellular stress processes that precede histological damage. For this we will use histological and biochemical methods in donated brain tissue from patients with early onset AD carrying PS1 E280A mutation comparing them with sporadic AD cases. Also we will search for correlations between cellular homeostasis markers findings and phenotypic differences within E280A cases. Results will help to understand the effect of PS1 mutations in cellular homeostasis and to generate a better characterization of AD neuropathology.18 páginas.spaInforme de investigaciónColcienciasRepositorio Colcienciashttp://colciencias.metabiblioteca.com.coinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2https://creativecommons.org/licenses/by/4.0/AutophagyBrain bankCellular homeostasis markersDementiasFamilial Alzheimer's diseaseMitochondrial StressProtein turnoverStress KinasesUnfolded protein response