title: Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease.
abstract: Besides the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles, neurogenesis and synaptic plasticity are markedly impaired in Alzheimer's disease (AD) possibly contributing to cognitive impairment. In this context, neurotrophic factors serve as a promising therapeutic approach via utilization of regenerative capacity of brain to shift the balance from neurodegeneration to neural regeneration. However, besides more conventional "bystander" effect, to what extent can neurotrophic compounds affect underlying AD pathology remains questionable. Here we investigated the effect of chronic oral treatment with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGL(A)G-NH2), on disease pathology both at moderate and severe stages in a transgenic mouse model of AD. 3xTg-AD and wild type female mice were treated for 12months with P021 or vehicle diet starting at 9-10months of age. A significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology associated sites was observed. The effect of P021 on Aβ pathology was limited to a significant decrease in soluble Aβ levels and a trend towards reduction in Aβ plaque load in CA1 region of hippocampus, consistent with reduction in Aβ generation and not clearance. This disease modifying effect was probably via increased brain derived neurotrophic factor (BDNF) expression mediated decrease in glycogen synthase kinase-3-β (GSK3β) activity we found in P021 treated 3xTg-AD mice. P021 treatment also rescued deficits in cognition, neurogenesis, and synaptic plasticity in 3xTg-AD mice. These findings demonstrate the potential of the neurotrophic peptide mimetic as a disease modifying therapy for AD.
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA; Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; SUNY-IBR Center for Developmental Neuroscience (CDN), 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: Faraz.Syed@downstate.edu.
authors.forename: Syed Faraz
authors.initials: SF
authors.lastname: Kazim
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: julie.blanchard.ibr@gmail.com.
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: charliedai78@yahoo.com.
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Dai
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: yunnchyn@yahoo.com.
authors.forename: Yunn-Chyn
authors.initials: YC
authors.lastname: Tung
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurobiological Disorders (UCI-MINDS), University of CA, Irvine 92697, USA. Electronic address: laferla@uci.edu.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: i_g_iqbal@yahoo.com.
authors.forename: Inge-Grundke
authors.initials: IG
authors.lastname: Iqbal
authors.affiliation: Department of Neurochemistry, Inge-Grundke Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Electronic address: khalid.iqbal.ibr@gmail.com.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D001814:Blood-Testis Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; D053764:Presenilin-1; C000595095:peptide 021; D016875:tau Proteins
keywords: Alzheimer's disease; Amyloid beta; Brain derived neurotrophic factor (BDNF); Ciliary neurotrophic factor (CNTF) derived peptide; Cognition; Dendritic and synaptic plasticity; Glycogen synthase kinase-3-beta (GSK3β); Neurogenesis; Tau hyperphosphorylation