Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Amitriptyline-mediated cognitive enhancement in aged 3xTg 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 (A) 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 (3xTgAD). 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 A monomer with a concomitant decrease in toxic oligomer A load, compared to vehicle-treated 3xTgAD 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. Male 3xTgAD mice, 14 months of age, were maintained on a 12hr light dark cycle in pathogen free conditions. Animals received food and water ad libitum. The test group received 100ug/g body weight amitriptyline-hydrochloride per os in their drinking water (Sigma-Aldrich, St. Louis MO) for 4 months (n = 15), and the control group received water (n = 15). The Hippocampus and Cortex were removed from 3 replicates of each group and RNA purification was done using glass bead disruption followed by the RNEasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. The RNA was examined for quantity and quality using an Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, CA). The samples were hybridized to Illumina's SentrixMouse Ref-8 v2. Expression BeadChips (Illumina, San Diego, CA).

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Becker

PROVIDER: E-GEOD-26836 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.

Chadwick Wayne W Mitchell Nick N Caroll Jenna J Zhou Yu Y Park Sung-Soo SS Wang Liyun L Becker Kevin G KG Zhang Yongqing Y Lehrmann Elin E Wood William H WH Martin Bronwen B Maudsley Stuart S

PloS one 20110627 6

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 th ...[more]

PMID: 21738757

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Dataset Information

Amitriptyline-mediated cognitive enhancement in aged 3xTg Alzheimer’s disease mice is associated with neurogenesis and neurotrophic activity

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Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.

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