Secreted amyloid-beta precursor protein function identified!

Alzheimer's-affected brains are riddled with so-called amyloid plaques: protein aggregates consisting mainly of amyloid-β. However, this amyloid-β is a fragment produced from a precursor protein whose normal function has remained enigmatic for decades. A team of scientists has now uncovered that this amyloid precursor protein modulates neuronal signal transmission through binding to a specific receptor. Modulating this receptor could potentially help treat Alzheimer's or other brain diseases. The results are published in Science.

More than 30 years have passed since the amyloid precursor protein was first identified. In the late 1980s, several research teams across the globe traced the protein fragment found in amyloid plaques back to a gene located on chromosome 21. The gene encodes a longer protein that is cleaved into several fragments, one of which ends up in amyloid plaques.

Decades of research have focused on the cleavage process that leads to the formation of the amyloid-β fragment and its subsequent aggregation, in the hope of identifying new therapeutic avenues for Alzheimer's. Meanwhile, an important question remained unanswered: what does the rest of the amyloid precursor protein actually do?

To answer this question, researchers set out to identify the nerve cell receptor that interacts with the amyloid precursor protein. "We knew that the amyloid precursor protein exerts its role through the part of the protein that is released outside of the cell. To understand its function, we needed to look for binding partners located on the cell surface," explains the lead author.'

The researchers identified a receptor present at the synapse, the structure where two different neurons connect to pass on signals. "We found that the secreted part of the amyloid precursor protein interacts with a receptor called GABABR1a, and that this in turn suppressed neuronal communication at the synapse," says the author.

Authors show that recombinant sAPPα selectively binds to GABABR subunit 1a (GABABR1a)–expressing cells. Binding was mediated by the flexible, partially structured extension domain in the linker region of sAPP and the natively unstructured sushi 1 domain specific to GABABR1a. sAPPβ and sAPPη, which both contain the extension domain, also bound to GABABR1a-expressing cells. Conversely, APP family members APP-like proteins 1 and 2, which lack a conserved extension domain, failed to bind GABABR1a-expressing cells.

Acute application of sAPPα reduced the frequency of mEPSCs and mIPSCs and decreased synaptic vesicle recycling in cultured mouse hippocampal neurons. In addition, sAPPα enhanced short-term facilitation in acute hippocampal slices from mice. Together, these findings demonstrate that sAPP reduces the release probability of synaptic vesicles.

These effects were dependent on the presence of the extension domain in sAPP and were occluded by a GABABR antagonist. A short APP peptide corresponding to the GABABR1a binding region within APP stabilized the natively unstructured sushi 1 domain of GABABR1a, allowing determination of its solution structure using nuclear magnetic resonance spectroscopy and the generation of a structural model of the APP–sushi 1 complex.

Application of a 17–amino acid APP peptide mimicked the effects of sAPPα on GABABR1a-dependent inhibition of synaptic vesicle release and reversibly suppressed spontaneous neuronal activity in vivo.