title: GFAP expression and social deficits in transgenic mice overexpressing human sAPPα.
abstract: Autistic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPPα), the product of α-secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPPα protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPPα and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPPα levels were observed in brains of autistic patients compared to controls. Transgenic mice engineered to overexpress human sAPPα (TgsAPPα mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP) expression, and altered Notch1 and IL-6 levels. NSCs isolated from TgsAPPα mice, and those derived from wild-type mice treated with sAPPα, displayed suppressed β-tubulin III and elevated GFAP expression. These results suggest that elevations in brain sAPPα levels are observed in subsets of individuals with autism and TgsAPPα mice display signs suggestive of gliosis and behavioral impairment.
authors.affiliation: Department of Psychiatry and Neurosciences, Rashid Laboratory for Developmental Neurobiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33613, USA.
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Bailey
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Demian F
authors.initials: DF
authors.lastname: Obregon
authors.forename: Samantha
authors.initials: S
authors.lastname: Portis
authors.forename: Steven
authors.initials: S
authors.lastname: Barger
authors.forename: Doug
authors.initials: D
authors.lastname: Shytle
authors.forename: Saundra
authors.initials: S
authors.lastname: Stock
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Paul G
authors.initials: PG
authors.lastname: Sanberg
authors.forename: Tanya
authors.initials: T
authors.lastname: Murphy
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001321:Autistic Disorder / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011595:Psychomotor Agitation / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism; D012920:Social Behavior Disorders / Q000235:genetics*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D051881:Receptor, Notch1; D050822:Cytokine Receptor gp130; D053829:Amyloid Precursor Protein Secretases
keywords: IL-6; Notch; astrogliosis; autism; behavior; sAPPα