Neurobiological bases of the degenerative dementias treatment

Abstract

Many biologic processes require a balance between the proteases that iniciate the proteolytic pathways essencial to life and inhibitors that limit excessive protease activity. The proteases having a complex mechanisms of action that involves a drastic change in their shape. Conformational changes not only inhibits the protease functions but also prepares it for destruction. Genetic or adquiring abnormalities that affecting a the protein structure, particularly in the mobile regions of the molecule, is a predisposition to the aggregation of aberrant forms of individual proteins. This pathogenic mechanism has special relevance in neurodegenerative disorders with dementia, including Alzheimer’s disease, spongiform encephalopathies, some forms of Parkinson’s disease, or familial dementia associated with the accumulation of a brain neuroserpin. Pathologic polymerization and accumulation of the insoluble fibrilar protein residues resistant to proteases degradation (β-amyloid, prion protein, α-synucleine, neuroserpine) develop cascades of toxic events with disregulation of cellular homeostasis (calcium, oxidative stress, glutamate, etc.) and neuronal degeneration.

The anticipated interference for to prevention of the formation and accumulation of oligomers and polymers with competitive agents and to stimulate clearance of the peptide from the brain with immunization is the mayor pharmacological challenge. Others therapeutic strategies aimed at ameliorating the pathogenesis of the disease.