AUTHOR=Sokol Deborah K. , Lahiri Debomoy K. 

TITLE=APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 16 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1201744

DOI=10.3389/fnmol.2023.1201744

ISSN=1662-5099

ABSTRACT=Metabolites of the Amyloid- precursor protein (APP) proteolysis may underlie brain overgrowth in Autism Spectrum Disorder (ASD). We have found elevated APP metabolites (total APP, secreted (s) APP, and -secretase adamalysins in the plasma and brain tissue of children with ASD. In this review, we highlight several lines of evidence supporting APP metabolites' potential contribution to macrocephaly in ASD. First, APP appears early in corticogenesis, placing APP in a prime position to accelerate growth in neurons and glia. APP metabolites are upregulated in neuroinflammation, another potential contributor to excessive brain growth in ASD. APP metabolites appear to directly affect translational signaling pathways, which have been linked to single gene forms of syndromic ASD (Fragile X Syndrome, PTEN, Tuberous Sclerosis Complex). Finally, APP metabolites and microRNA, which regulates APP expression, may contribute to ASD brain overgrowth, particularly increased white matter, through ERK receptor activation on the PI3K/Akt/mTOR/Rho GTPase pathway, favoring myelination.The intersection of ASD with Alzheimer's disease (AD) has been of recent interest, and APP has been at the center of that interest. We review the large heads/macrocephaly finding in ASD and the mechanisms suggested to underly this finding. We propose that the metabolites associated with the nonamyloidogenic pathway, i.e., secreted (s) APP and -secretase adamalysins, microRNA, contribute to brain overgrowth in ASD. Specifically, we propose an integrated pathway, beginning with the overproduction of sAPP that activates the PI3K/Akt/mTOR/Rho GTPase pathway resulting in increased white matter in ASD.