Alzheimer's disease (AD) is a progressive dementia that presents dysfunction and neurodegeneration of specific brain areas, leading to a severe memory loss, inability to form new memories and damage to other cognitive abilities. One of the main neuropathological features of this disorder is the formation of extracellular amyloid plaques, which contain mainly beta-amyloid peptide (Abeta). The oligomers of Abeta (A²O) are pathogenic ligands of synapses, which affect synaptic plasticity, memory formation and inhibit long-term potentiation. A large number of genetic and neuropathological similarities between AD and prion diseases have been described. The prion protein (PrPc) is a glycoprotein anchored to the plasma membrane that binds to extracellular matrix proteins such as laminin, inducing axonal growth, neuronal adhesion and neuritogenesis. In addition, PrPc interacts with the secreted co-chaperone STI1 (Stress inducible protein 1) inducing neuroprotection and neuritogenesis and also modulating memory formation. Recently, it was reported that PrPC is a receptor for A²O, however, the functionality and the mechanisms involved in this interaction have not yet been elucidated. The main objectives of this project are to test the possible neuroprotective effects of STI1, and laminin against A²O-mediated toxicity, and the involvement of PrPC in this process. These objectives will be addressed by examining the levels of synaptic proteins and total protein synthesis in neurons exposed to A²O. We also intend to identify multiprotein complexes associated with PrPc after treatment with A²O, identifying binding partners common to both PrPc and A²O. Additionally, the behavioral profile of transgenic animals that present the pathogenic features of AD treated with STI1 and laminin, will be analyzed. The use of PrPC ligands like STI1 and laminin as tools to interfere with the toxic effects caused by A²O are important instruments in the study of the AD pathology and point to new therapeutic possibilities.
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