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The Journal of Neuroscience, September 2, 2009, 29(35):10788-10801; doi:10.1523/JNEUROSCI.2132-09.2009

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Neurobiology of Disease
Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis

Zilai Wang,^1,2 * Baiping Wang,^1 * Li Yang,¹ Qinxi Guo,^1,6 Nadia Aithmitti,¹ Zhou Songyang,³ and Hui Zheng^1,2,4,5,6

¹Huffington Center on Aging, Departments of ²Molecular and Human Genetics, ³Biochemistry and Molecular Biology, ⁴Molecular and Cellular Biology, and ⁵Neuroscience, and ⁶Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: huiz{at}bcm.edu

A critical role of the amyloid precursor protein (APP) in Alzheimer's disease (AD) pathogenesis has been well established. However, the physiological function of APP remains elusive and much debated. We reported previously that the APP family of proteins is essential in mediating the developing neuromuscular synapse. In the current study, we created a conditional allele of APP and deleted APP in presynaptic motor neuron or postsynaptic muscle. Crossing these alleles onto the APP-like protein 2-null background reveals that, unexpectedly, inactivating APP in either compartment results in neuromuscular synapse defects similar to the germline deletion and that postsynaptic APP is obligatory for presynaptic targeting of the high-affinity choline transporter and synaptic transmission. Using a HEK293 and primary hippocampus mixed-culture assay, we report that expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons. This activity is dependent on neuronal APP and requires both the extracellular and intracellular domains; the latter forms a complex with Mint1 and Cask and is replaceable by the corresponding SynCAM (synaptic cell adhesion molecule) sequences. These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule. We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis.

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Received May 5, 2009; revised July 6, 2009; accepted July 16, 2009.

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: huiz{at}bcm.edu

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