title: Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.
abstract: Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
authors: Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors: Wayne
authors: W
authors: Chadwick
authors: Nick
authors: N
authors: Mitchell
authors: Jenna
authors: J
authors: Caroll
authors: Yu
authors: Y
authors: Zhou
authors: Sung-Soo
authors: SS
authors: Park
authors: Liyun
authors: L
authors: Wang
authors: Kevin G
authors: KG
authors: Becker
authors: Yongqing
authors: Y
authors: Zhang
authors: Elin
authors: E
authors: Lehrmann
authors: William H
authors: WH
authors: Wood
authors: Bronwen
authors: B
authors: Martin
authors: Stuart
authors: S
authors: Maudsley
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000639:Amitriptyline / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline