title: Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model.
abstract: Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to beta-amyloid (Abeta) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain Abeta deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.
authors.affiliation: Department of Veterans Affairs Medical Center, Richmond, Virginia 23249, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.forename: Aimin
authors.initials: A
authors.lastname: Qiao
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Wang
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Goodwin
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Lee
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
authors.forename: Matthew
authors.initials: M
authors.lastname: Allsbrook
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDonald
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000970:Antineoplastic Agents; D005904:Glial Fibrillary Acidic Protein; D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D014212:Tretinoin; D051360:Cyclin-Dependent Kinase 5