Abstract

One of the greatest challenges in medicine during the past two decades has been to tackle the pathogenesis of Alzheimer's disease. Major advances have been made based onthe development of what we know today as modern molecular medicine. This neuropsychiatric disorder is characterized by the formation in the brain of two main types of protein aggregates: (i) neurofibrillary tangles, formed by the association of helical paired filaments, which are the product of the self-polymerization of the microtubule-associated protein tau (ii) ?-amyloid deposits of the A? peptide that form senile plaques. The evidence accumulated in the last years emphasizes the role of hyperphosphorylations of tau protein at the intraneuronal level, as a central event in the pathogenesis of Alzheimer neurodegeneration. Recent investigations in our laboratory led to the discovery that the deregulation of the protein kinase system cdk5/p35 is determinant for tau hyperphosphorylations. These findings led to a series of investigations to explain the alteration that occurs in the cascade of molecular signaling leading to a loss of cdk5 regulation. Alterations in other protein kinases such as Gsk3? have also been studied. Factors such as A? deposition, oxidative stress and inflammatory processes have been shown to trigger major alterations, sometimes irreversible, in the normal signaling pathways, thus generating a dysfunction in brain neurons, especially in the hippocampus, eventually leading to neuronal death in the late stages of the disease. In this study, we analyze the relationship between the extraneuronal factors that determined the deregulation in protein kinase signaling pathways and the modifications of tau protein, a central paradigm in Alzheimer's pathology. © 2006 Sociedad de Neurología, Psiquiatría y Neurocirugía.