title: Discoveries in Down syndrome: moving basic science to clinical care.
abstract: This review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development of pharmacological restoration of cognitive function in people with this developmental disorder. Changes in structure and function of synaptic connections within the hippocampal formation of DS model mice, as well as alterations in innervations of the hippocampus by noradrenergic and cholinergic neuromodulatory systems, provided important clues for potential pharmacological treatments of cognitive disabilities in DS. Possible molecular and cellular mechanisms underlying this genetic disorder have been addressed. We discuss novel mechanisms engaging misprocessing of amyloid precursor protein (App) and other proteins, through their affect on axonal transport and endosomal dysfunction, to "Alzheimer-type" neurodegenerative processes that affect cognition later in life. In conclusion, a number of therapeutic strategies have been defined that may restore cognitive function in mouse models of DS. In the juvenile and young animals, these strategists focus on restoration of synaptic plasticity, rate of adult neurogenesis, and functions of the neuromodulatory subcortical systems. Later in life, the major focus is on recuperation of misprocessed App and related proteins. It is hoped that the identification of an increasing number of potential targets for pharmacotherapy of cognitive deficits in DS will add to the momentum for creating and completing clinical trials.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. akleschevnikov@yahoo.com
authors.forename: A M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.forename: P V
authors.initials: PV
authors.lastname: Belichenko
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.forename: C
authors.initials: C
authors.lastname: Wu
mesh_terms: D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics / Q000628:therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D057170:Translational Research, Biomedical
chemical_list: D016564:Amyloid beta-Protein Precursor