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How autism and Alzheimer’s disease are TrAPPed

Molecular Psychiatry volume 26, pages 26–29 (2021)Cite this article

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This Comment posits that two important psychiatric disorders, autism spectrum disorder (ASD) and Alzheimer’s disease (AD), typical to opposite ends of the lifespan (early vs late), neuroanatomy (enlarged vs reduced amygdala), biochemistry (low vs high amyloid-β peptide), and outcomes (neurotrophic vs neurodegeneration) [1], are molecularly in opposition specifically through metabolites of amyloid-β precursor protein (APP). Herein, we  attempt to address associated regulatory questions.

When considering contributing factors to AD, APP and its cleavage products are “usual suspects”. This is through the amyloidogenic processing pathway, involving sequential proteolytic cleavages of APP by β-secretase (β-site APP cleaving enzyme 1, BACE1) and γ-secretase complexes. The constitutive APP processing pathway, on the other hand, by sequential action of α- and γ-secretases, produces the secreted cleavage products sAPPα (and non-amyloidogenic p3 peptide), which function as neurotrophic factors that contribute to neurite growth and neuroproliferation, and synaptogenesis [3] and as an iron export protein [4]. This elevation of sAPPα associates with ASD [5]. Animal models also support a link. For example transgenic mice over-expressing sAPPα, have elevated glial fibrillary acidic protein in brain and notable social deficits [6]. The amyloidogenic pathway generates the potentially toxic amyloid-β (Aβ) peptide, which can aggregate in extraneuronal plaques in AD. However, Aβ does not exist solely to cause disease and has normal neurological functions [7]. The constitutive pathway is important for neurodevelopmental disorders, such as ASD. Notably, p3 peptide (called “N-terminally truncated Aβ”) is elevated in ASD [8], and Aβ is reduced in ASD [9] but elevated in AD. The findings of sAPPα elevation [10] and Aβ reduction [11] have been replicated by independent laboratories in human subjects with autism.

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Fig. 1: Autism and Alzheimer’s disease-APP function TrAPPed in place.

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request

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Acknowledgements

We thank grant supports from the National Institute on Aging, NIH (NIA)  (R01AG051086 and R21AG4687100- PI: DKL) as well as from the Indiana Alzheimer’s Disease Research Center, NIA (P30AG010133).

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Authors and Affiliations

  1. Department of Psychiatry and Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    Debomoy K. Lahiri, Bryan Maloney & Ruizhi Wang

  2. Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Debomoy K. Lahiri

  3. Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Debomoy K. Lahiri & Bryan Maloney

  4. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

    Deborah K. Sokol

  5. Department of Psychiatry, Neurochemistry lab, MGH, Harvard Medical School, Charlestown, MA, USA

    Jack T. Rogers

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

    Cara J. Westmark

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  1. Debomoy K. Lahiri
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Correspondence to Debomoy K. Lahiri.

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Lahiri, D.K., Maloney, B., Wang, R. et al. How autism and Alzheimer’s disease are TrAPPed. Mol Psychiatry 26, 26–29 (2021). https://doi.org/10.1038/s41380-020-00928-8

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