title: Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.
abstract: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-β (Aβ) precursor protein (APP) and metabolites are usually associated with Alzheimer's disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. β-site APP cleaving enzyme (BACE1) cleavage produces secreted APPβ (sAPPβ) and intact Aβ. Excess Aβ is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPα in ASD and FXS vs.
  
  
  
  We now report elevated plasma Aβ and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPα in ASD and FXS vs.
  
  
  
  By contrast, plasma and brain sAPPβ and Aβ were lower in ASD vs. controls but elevated in FXS plasma vs.
  
  
  
  We also detected age-dependent increase in an α-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.
authors.affiliation: Indiana University School of Medicine, Departments of Psychiatry, Indianapolis, Indiana-46202, USA.
authors.forename: Balmiki
authors.initials: B
authors.lastname: Ray
authors.affiliation: Indiana University School of Medicine, Departments of Neurology, Indianapolis, Indiana-46202, USA.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Sokol
authors.affiliation: Indiana University School of Medicine, Departments of Psychiatry, Indianapolis, Indiana-46202, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Maloney
authors.affiliation: Indiana University School of Medicine, Departments of Psychiatry, Indianapolis, Indiana-46202, USA.|Indiana University School of Medicine, Departments of Medical and Molecular Genetics, Institute of Psychiatric Research, Indianapolis, Indiana-46202, USA.|Indiana Alzheimer Disease Center, Indianapolis, Indiana-46202, USA.
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000679:Amygdala / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D000067877:Autism Spectrum Disorder / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005600:Fragile X Syndrome / Q000378:metabolism*; D006801:Humans; D009928:Organ Specificity; D010949:Plasma / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human