Obtención recombinante de fragmentos variables de cadena sencilla rediseñados racionalmente como agentes terapeuticos para el tratamiento de la enfermedad de Alzheimer

Alzheimer Disease affected to some 24 millions of people in 2001, and is estimated to affect to some 81 millions in 2040. Present therapy takes advantage of acetylcholine esterase and glutamate receptor inhibitors providing just a palliative effect. One of the main features concerning Alzheimerpathology is the extra-cellular deposition of amyloid plaques composed by ordered aggregates of peptide A\beta. Effectiveness of peptide A\beta-directed antibodies removing amyloid plaques has been tested until Phase 2a, moment in which neuroinflamatory complications appeared within 6% of immunized patients. The relationship between opsonizationof amyloid deposits and microglia activation points out proinflammatory factors secretion as the inductor of neuroinflamation. The present project proposes the redesign of humanized monoclonal antibodies, already reportedin the literature, in orden to obtain single-chain variable fragments that, maintaining -ideally improving- inhibition properties on the formation of amyloid fibrils, and the capability to disaggregate preformed plaques, do not activate the microglia pathway. Present methodology in recombinant expression and design of proteins, together with the ongoing knowledge on protein conformational changes driven amyloid fibril formation, allows to redesign proteins in order to increase solubility and stability, and in turn, to improve biological activities. Such a kind of redesigned molecule should be effective at lower doses. Undertaking Alzheimer Disase from the molecular redesign approach is a great challenge to the cure of this hihg social-impact disease.