USE OF CALCILYTIC DRUGS AS A PHARMACOLOGICAL APPROACH TO THE TREATMENT AND PREVENTION OF ALZHEIMER'S DISEASE, ALZHEIMER'S DISEASE-RELATED DISORDERS, AND DOWN'S SYNDROME NEUROPATHIES

摘要

A pharmacological treatment of both familial early onset and sporadic late onset Alzheimer's disease (AD), AD-related disorders and Down's syndrome-coupled neuropathies involves the use of a class of drugs, the calcilytics, which by inhibiting the calcium-sensing receptor (CaSR)signaling in all types of brain cells prevent: (i) the overproduction of cell-harming nitric oxide (NO) and peroxynitrite (ONOO^-), and most importantly (ii) the intracellular overproduction, accumulation, and secretion of Amyloid β (Aβ) peptides in response to the extracellular presence of exogenous Aβpeptides and/or proinflammatory cytokines, and (iii) the Aβ peptide-related hyperphosphorylation of the Tau (τ) protein on the part of an Aβ/Ca SR-signaling activated glycogen synthase kinase-(GSK)-3β w i t h the resulting formation of neurofibrillary tangles (NTFs), the latter known to cause such severe dysfunctioning of the microtubular cytoskeleton as to eventually favor (iv) the death of human cerebral cortex neurons.