PMID- 25046994 OWN - NLM STAT- MEDLINE DCOM- 20150602 LR - 20220309 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 71 DP - 2014 Nov TI - Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. PG - 110-30 LID - S0969-9961(14)00195-8 [pii] LID - 10.1016/j.nbd.2014.07.001 [doi] AB - Besides the presence of amyloid beta (Abeta) 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 Abeta pathology was limited to a significant decrease in soluble Abeta levels and a trend towards reduction in Abeta plaque load in CA1 region of hippocampus, consistent with reduction in Abeta 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-beta (GSK3beta) 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Kazim, Syed Faraz AU - Kazim SF AD - 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. FAU - Blanchard, Julie AU - Blanchard J AD - 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. FAU - Dai, Chun-Ling AU - Dai CL AD - 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. FAU - Tung, Yunn-Chyn AU - Tung YC AD - 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. FAU - LaFerla, Frank M AU - LaFerla FM AD - 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. FAU - Iqbal, Inge-Grundke AU - Iqbal IG AD - 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. FAU - Iqbal, Khalid AU - Iqbal K AD - 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. LA - eng PT - Journal Article DEP - 20140715 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Antipsychotic Agents) RN - 0 (Ciliary Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (Presenilin-1) RN - 0 (peptide 021) RN - 0 (tau Proteins) SB - IM MH - Administration, Oral MH - Alzheimer Disease/*drug therapy/genetics/pathology MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Antipsychotic Agents/*administration & dosage/blood/chemistry MH - Blood-Testis Barrier/drug effects/physiology MH - Brain/*drug effects MH - Cells, Cultured MH - Ciliary Neurotrophic Factor/*administration & dosage/blood/chemistry MH - Disease Models, Animal MH - Enzyme Inhibitors/pharmacology MH - Female MH - Gene Expression Regulation/drug effects/genetics MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurons/drug effects MH - Presenilin-1/genetics MH - Signal Transduction/drug effects/genetics MH - Time Factors MH - tau Proteins/genetics OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid beta OT - Brain derived neurotrophic factor (BDNF) OT - Ciliary neurotrophic factor (CNTF) derived peptide OT - Cognition OT - Dendritic and synaptic plasticity OT - Glycogen synthase kinase-3-beta (GSK3beta) OT - Neurogenesis OT - Tau hyperphosphorylation EDAT- 2014/07/23 06:00 MHDA- 2015/06/03 06:00 CRDT- 2014/07/23 06:00 PHST- 2014/01/26 00:00 [received] PHST- 2014/05/28 00:00 [revised] PHST- 2014/07/08 00:00 [accepted] PHST- 2014/07/23 06:00 [entrez] PHST- 2014/07/23 06:00 [pubmed] PHST- 2015/06/03 06:00 [medline] AID - S0969-9961(14)00195-8 [pii] AID - 10.1016/j.nbd.2014.07.001 [doi] PST - ppublish SO - Neurobiol Dis. 2014 Nov;71:110-30. doi: 10.1016/j.nbd.2014.07.001. Epub 2014 Jul 15.