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Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism

Molecular Psychiatry volume 21, pages 1333–1341 (2016)Cite this article

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Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aβ) precursor protein (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on β-secretase (amyloidogenic) processing and the accumulation of Aβ peptides in adult FXS models, whereas Lahiri and Sokol have studied α-secretase (non-amyloidogenic or anabolic) processing and altered levels of sAPPα and Aβ in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer’s disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging.

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Acknowledgements

We thank the reviewers for their careful and insightful critiques, which greatly improved the manuscript. CJW has received funding from FRAXA Research Foundation, NIH (R21AG044714 and R03HD075881), the University of Wisconsin (UW)-Madison Alzheimer’s Disease Research Center (NIA P50AG033514), the UW-Madison Clinical and Translational Science Award (CTSA) program (NCATS UL1TR000427), Lundbeck USA, Merz Pharmaceuticals and Pierre Fabre. DKS has received funding from the Riley Memorial Foundation, Mental Health Association for the Advancement of Mental Health Research and Education, Clarian Health Partners, Indiana University Collaborative Research Grant (22-140-29). DKL has received funding from NIH (R01AG051086, R21AG4687100, P30AG010133), Alzheimer’s Association, Indiana Clinical and Translational Sciences Institute (ICTSI), and ISDH Spinal Cord and Brain Injury Board.

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Author notes

  1. C J Westmark and D K Sokol: Co-first authors.

Authors and Affiliations

  1. Department of Neurology, University of Wisconsin, Madison, WI, USA

    C J Westmark

  2. Department of Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    D K Sokol

  3. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    B Maloney & D K Lahiri

  4. Department of Medical & Molecular Genetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    D K Lahiri

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  1. C J Westmark
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  2. D K Sokol
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  3. B Maloney
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  4. D K Lahiri
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Correspondence to C J Westmark or D K Lahiri.

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Competing interests

DKL reports grants as a Principal Investigator from the National Institute on Aging, National Institute of Health, USA; Member, Scientific Advisory Board, QR Pharma, Berwyn, PA, USA; Member, Scientific Advisory Board, Yuma Therapeutics, Boston, MA; Member, Scientific Advisory Board, Entia Biosciences, Sherwood, OR; Member, International Advisory Board of the Drug Discovery and Therapy World Congress, Boston, MA; and Editor-in-Chief, ‘Current Alzheimer Research’, Bentham Sciences Publishers. The remaining authors declare no conflict of interest.

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Westmark, C., Sokol, D., Maloney, B. et al. Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism. Mol Psychiatry 21, 1333–1341 (2016). https://doi.org/10.1038/mp.2016.134

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  • DOI: https://doi.org/10.1038/mp.2016.134

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