• Syed Faraz Kazim, Julie Blanchard, Chun-Ling Dai, Yunn-Chyn Tung, Frank M LaFerla, Inge-Grundke Iqbal, and Khalid Iqbal.
• 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.
• Neurobiol. Dis. 2014 Nov 1;71:110-30.

AbstractBesides 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.Copyright © 2014 Elsevier Inc. All rights reserved.

49 keywords...

hide…