Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway

Abstract

Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer’s disease (AD) associated amyloid-β precursor protein (APP), especially its neuroprotective processing product, secreted APP α, is elevated in persons with autism. This has led to the “anabolic hypothesis” of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP’s involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP’s contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

“…FXS is a neurodevelopmental disorder and patients with FXS have a high incidence of ASD. Children with severe autism and Fragile X express elevated levels of sAPPa (Erickson et al, 2014;Ray et al, 2011), consistent with the hypothesis for a sAPPa-mediated anabolic pathway in ASD (Lahiri et al, 2013). Therefore, it is tempting to hypothesize that alteration of the APP non-amyloidoigenic pathway might be a shared feature of several neurodevelopmental disorders.…”

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

“…There are distinct brain abnormalities as well as cellular and neurochemical pathways found in ASD, FXS and AD subjects. In this context, we have recently proposed that anabolic excess may result in a gain of function overgrowth associated with elements of neurodevelopmental conditions, while catabolic excess would be associated with neurodegeneration (Lahiri et al, 2013). Higher levels of sAPPα and lower levels of a potentially toxic Aβ peptide are observed in plasma and brain tissue of children with severe autism.…”

“…Biomarker development in autism, while the focus of significant research, has been met with limited success to date. In this context, we have previously reported higher levels of secreted amyloid-β precursor protein-alpha form (sAPPα) and lower levels of potentially toxic amyloid-β (Aβ) peptide in plasma and brain tissue of children with severe autism (Sokol et al, 2006; Sokol et al, 2011; Lahiri et al, 2013). How sAPPα mediates cell signaling relevant to ASD remains a major unanswered question, and the present work could shed some lights on this knowledge gap in the field.…”

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

“…These findings may provide new directions, by performing an accurate quantification of various APP-mRNA in brain tissues, for the research of early-onset AD from the first AD patient, Auguste D., in whom the disease was discovered. Recently, an increased secreted soluble APP derivative from the cleavage by α-secretase (APPsα fragment) in the plasma of severely autistic patients has been reported (143)(144)(145)(146). These authors speculated that overproduction of APPsα may contribute to the state of brain overgrowth implicated in autism and FXS.…”