title: Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer's-like memory deficits in the Ts65Dn mouse model of Down syndrome.
abstract: Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of intellectual disability and is associated with a greatly increased risk of early-onset Alzheimer's disease (AD). The Ts65Dn mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment. Accumulating evidence suggests that impairments in early brain development caused by trisomy 21 contribute significantly to memory deficits in adult life in DS. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. Here, we report that prenatal to early postnatal treatment with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life in Ts65Dn mice. Furthermore, this treatment prevented pre-synaptic protein deficit, decreased glycogen synthase kinase-3beta (GSK3β) activity, and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (~ 7-month-old) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments in a DS mouse model.
authors.affiliation: Department of Neurochemistry, and SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY 10314, USA.|The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY 11203, USA.|Graduate Program in Neural and Behavioral Science, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Syed Faraz
authors.initials: SF
authors.lastname: Kazim
authors.affiliation: Department of Neurochemistry, and SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY 10314, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Department of Neurochemistry, and SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY 10314, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D002658:Developmental Disabilities / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications*; D005260:Female; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D011247:Pregnancy
chemical_list: D020934:Ciliary Neurotrophic Factor; C000595095:peptide 021