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. controls. 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. controls. By contrast, plasma and brain sAPPβ and Aβ were lower in ASD vs. controls but elevated in FXS plasma vs. controls. 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.
Highlights
Autism spectrum disorder (ASD) is a developmental disorder with a complex etiology
The proteolytic cleavage of Amyloid-βprecursor protein (APP) via the α-secretase pathway releases neurotrophic secreted APPα (sAPPα)12,15 (Fig. 1). An excess in this pathwaymay result in a gain of function overgrowth and anabolic state associated with neurodevelopmental conditions[16], while the expected plasma neuronal marker profile in Alzheimer’s disease (AD) is low sAPPαand high amyloid-β peptide (Aβ).Our goal is to provide a biochemical basis to explain common features and differences between ASD and Fragile X syndrome (FXS) regarding neurobiology, neuroanatomy, and behavior
We report a consistent increase in protein levels of sAPPαaccompanied by decreased sAPPβand Aβin ASD vs. neurotypical controls
Summary
Autism spectrum disorder (ASD) is a developmental disorder with a complex etiology. It is characterized by persistent deficits in social communication and social interaction across multiple contexts and restricted, repetitive patterns of behavior, interests, or activities. The proteolytic cleavage of APP via the α-secretase pathway releases neurotrophic sAPPα12,15 (Fig. 1) An excess in this pathway (sAPPαand low Aβ)may result in a gain of function overgrowth and anabolic state associated with neurodevelopmental conditions[16], while the expected plasma neuronal marker profile in AD is low sAPPαand high Aβ.Our goal is to provide a biochemical basis to explain common features and differences between ASD and FXS regarding neurobiology, neuroanatomy, and behavior. We found an increase in levels of sAPPα, sAPPβ, and Aβin FXS vs neurotypical controls in the few brain tissue samples available to us. These differences are significant between ASD and FXS. ASD is significantly lower than control. (C) Total APP levels in plasma
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