title: mTOR Hyperactivation in down syndrome hippocampus appears early during development.
abstract: The mammalian target of rapamycin (mTOR) signaling pathway is a key developmental pathway involved in mechanisms underlying cellular aging and neurodegeneration. We hypothesized that its deregulation may occur during early brain development in patients with Down syndrome (DS). The expression patterns and cellular distribution of components of mTOR signaling (phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR) were investigated in developing hippocampi from controls and patients with DS and from adults with DS and Alzheimer disease-associated pathology using immunocytochemistry. In control hippocampi, only phosphorylated S6 was detected prenatally (19-41 gestational weeks); it became undetectable 2 months postnatally. Increased expression of phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR was observed in DS hippocampus compared with controls. Phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. Prominent expression of mTOR components was observed in pyramidal neurons with granulovacuolar degeneration and in neurons containing neurofibrillary tangles in the hippocampi of DS subjects with Alzheimer disease pathology. These findings suggest that a dysregulated mTOR pathway may contribute to both early hippocampal developmental abnormalities and hippocampal functional impairment developing before neurodegeneration. Moreover, the expression patterns of mTOR components in adult DS hippocampus support its association with Alzheimer disease-related histopathologic changes.
authors.affiliation: From the Department of (Neuro)Pathology, Academic Medical Center (AMI, JvS, JJA, EA), and Swammerdam Institute for Life Sciences, Center for Neuroscience (EA), University of Amsterdam, Amsterdam; and Stichting Epilepsie Instellingen Nederland, Heemstede (EA), the Netherlands; Institute of Neurology, Medical University of Vienna, Vienna, Austria (IM, GGK); and Inserm UMR 676, Physiopathology and Neuroprotection of the Developing Brain, Robert Debré Hospital, Paris, France (HA-B).
authors.forename: Anand M
authors.initials: AM
authors.lastname: Iyer
authors.forename: Jackelien
authors.initials: J
authors.lastname: van Scheppingen
authors.forename: Ivan
authors.initials: I
authors.lastname: Milenkovic
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Anink
authors.forename: Homa
authors.initials: H
authors.lastname: Adle-Biassette
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001711:Biotransformation; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016612:Paraffin Embedding; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016707:Tissue Fixation; D055815:Young Adult
chemical_list: D046912:Multiprotein Complexes; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases