Pasciuto E, Ahmed T, Wahle T, Gardoni F, D'Andrea L, Pacini L, Jacquemont S, Tassone F, Balschun D, Dotti CG, Callaerts-Vegh Z, D'Hooge R, Müller UC, Di Luca M, De Strooper B, Bagni C. Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. Neuron. 2015 Jul 15;87(2):382-98. PubMed.

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  1. A role for FMRP as a translational repressor of APP has been reported earlier. Here the authors present the novel finding that ADAM10 is also a target of FMRP, and that ADAM10 levels increase when FMRP is absent. The combination of increased APP and ADAM10 synthesis in Fmr1 knockout mice leads to elevated sAPPα, which is responsible for the molecular, morphological, and functional deficits observed in the Fmr1 mutant mice and, by extension, Fragile X patients. This is significant in that it raises the intriguing possibility that abnormal APP production and APP processing could underlie both Fragile X, a neurodevelopmental disorder, and Alzheimer’s disease, the most common neurodegenerative disease in old age. However, several questions remain to be addressed: First, why does the regulation of APP and ADAM10 by FMRP only occur during a specific postnatal development stage? Second, what are the mechanisms linking sAPPα to mGluR5 signaling and protein translation? Lastly, do such sAPPα-mediated pathways also regulate neuronal function in adult and aged brains?

    While not related to the current study, it is interesting to note that APP is also overproduced in another intellectual disability disorder, Down’s syndrome (DS). Therefore, it is tempting to ask whether increased APP (and sAPPα) in DS could, through similar pathways revealed here, contribute to early neurological impairment in addition to the development of AD in later ages.  

    View all comments by Hui Zheng

  2. This Neuron paper by Pasciuto and colleagues describes the effects of dysregulated ADAM10-mediated processing of APP on Fragile X syndrome. Their evidence for the role of soluble APP alpha (sAPPα) in mediating immature spine, mRNA translation, and mGluR-LTD phenotypes in Fmr1KO mice dovetails nicely with recent studies regarding the role of non-amyloidogenic (α-secretase) processing of APP in autism (Sokol et al., 2006; Bailey et al., 2013; Ray et al., 2011; Lahiri et al., 2013). Their data also suggest that pharmacological inhibition of ADAM10 may be a viable therapeutic option for Fragile X.

    A caveat to these findings is that APP is also regulated by amyloidogenic (β-secretase) processing. Our laboratory observed elevated levels of Aβ in older Fmr1KO mice and rescue of numerous disease phenotypes in Fmr1KO/APPHET mice, which support testing β-secretase inhibitors in Fragile X (Westmark et al., 2007). The presence of elevated Aβ levels in older mice was reproduced in the current study, which went on to show that juvenile mice exhibit reduced levels of Aβ. Abnormal Aβ accumulation has also been observed in idiopathic and Dup15 autism brains in both adults and children (Wegiel et al., 2012; Al-Ayadhi et al., 2012). These studies contribute to a growing body of knowledge suggesting that APP processing is developmentally regulated and aberrant in both Fragile X and autism. Much remains to be learned regarding: (1) APP metabolite profiles as a function of age, (2) potential alterations in proteolytic processing of APP with development, and (3) associations between APP metabolite levels and Fragile X and autism traits. The current study contributes a substantial amount of data regarding the role of sAPPα in Fragile X, particularly during the early postnatal stage of development.

    From a therapeutic standpoint, it may be necessary to simultaneously modulate both α- and β-secretase processing to attain homeostatic levels of APP metabolites and rescue Fragile X phenotypes. We have observed that both overexpression and knockout of APP increases seizure propensity in juvenile Fmr1KO mice. Born and colleagues demonstrated that juvenile overexpression of APP contributes to sharp wave EEG discharges in APP transgenic mice; they did not differentiate between full-length APP and sAPPα (Born et al., 2014). And Prox and colleagues found that seizures are increased in the ADAM10 conditional knockout mouse (Prox et al., 2013). Seizures were not studied in the Pasciuto publication; thus, the role of ADAM10 and sAPPα on seizure propensity in the Fmr1KO remains to be determined. It is likely that various APP metabolites contribute to different fragile phenotypes. Of interest, numerous drugs currently under study for FXS may be effective due to off-site activities that modulate APP, Aβ, β-secretase and/or ADAM10. (Westmark et al., 2013; Erickson, 2014). For example, the acetylcholinesterase inhibitor donepezil (Aricept), which is used to treat Alzheimer’s disease, has been shown to improve cognitive-behavioral function in Fragile X (Kesler et al., 2009). Donepezil decreases Aβ levels (Dong et al., 2009) and increases ADAM10 activity and the release of sAPPα (Zimmerman, 2005).

    Overall, this exciting publication by the Bagni laboratory demonstrates important roles for ADAM10 and sAPPα in Fragile X pathology and provides a strong impetus for future studies to define the differential roles of APP metabolites during development and the therapeutic efficacy of secretase drugs in Fragile X syndrome.

    References:

    Sokol DK, Chen D, Farlow MR, Dunn DW, Maloney B, Zimmer JA, Lahiri DK. High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J Child Neurol. 2006 Jun;21(6):444-9. PubMed.

    Bailey AR, Hou H, Song M, Obregon DF, Portis S, Barger S, Shytle D, Stock S, Mori T, Sanberg PG, Murphy T, Tan J. GFAP expression and social deficits in transgenic mice overexpressing human sAPPα. Glia. 2013 Sep;61(9):1556-69. PubMed.

    Ray B, Long JM, Sokol DK, Lahiri DK. Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker. PLoS One. 2011;6(6):e20405. Epub 2011 Jun 22 PubMed.

    Lahiri DK, Sokol DK, Erickson C, Ray B, Ho CY, Maloney B. Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway. Front Cell Neurosci. 2013;7:94. PubMed.

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    Westmark CJ, Westmark PR, O'Riordan KJ, Ray BC, Hervey CM, Salamat MS, Abozeid SH, Stein KM, Stodola LA, Tranfaglia M, Burger C, Berry-Kravis EM, Malter JS. Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. PLoS One. 2011;6(10):e26549. PubMed.

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    View all comments by Cara Westmark

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