It's been 30 or so years since amyloid beta precursor protein (APP) was first pinpointed as the precursor of the amyloid beta (AB) peptide that is the main constituent of plaques found in the brains of Alzheimer's disease (AD) patients.

Since then, research has focused on the cleavage process that leads to the formation of A-beta fragments and their subsequent aggregation, in the hope of identifying new avenues for treating the neurodegenerative disease.

Meanwhile, the important question of what is the normal function of APP, was left hanging.

Now, researchers in Belgium have discovered APP modulates neuronal signal transmission by binding to a GABA (gamma-aminobutyric acid) receptor, suppressing neuronal communication at the synapse.

The scientists, led by Bart De Strooper, who in addition to being a professor at VIB-KU Leuven Center for Brain Disease & Research, is director of the UK Dementia Research Institute, based at University College London, said modulating the receptor represents a new therapeutic avenue to explore in AD and other neurological diseases.

"Although mutations in APP in familial cases of AD all affect the production of A-beta, we don't really know whether other aspects of the protein's function contribute to Alzheimer's as well," De Strooper said.

The new findings add a fresh perspective. "The newly identified role of APP may underlie neuronal network abnormalities we see in mouse models of AD and preceding clinical onset in human patients," said De Strooper. A drug targeting the GABA receptor might attenuate those abnormalities.

De Strooper and two of his co-authors are inventors on a patent on the interaction between APP and the GABA isoform they identified.

Although there was existing evidence that secreted APP affects synaptic transmission and plasticity, the cell-surface receptor through which it mediates its function was not known.

The researchers first confirmed APP is abundantly expressed in hippocampal synapses and then performed a series of experiments to pull down interacting proteins from synaptic fractions. Mass spectrometry analysis consistently identified the isoform GABA type B receptor subunit 1 (GABABR1a), as the most abundant cell-surface protein.

The proteomics results were validated in cell surface binding assays, showing APP binds directly and selectively to GABABR1a with submicromolar affinity.

On binding, APP was shown to suppress synaptic vesicle release, modulating hippocampal synaptic plasticity and reducing neurotransmitter release.

Heather Rice, co-author of the paper, published in the Jan. 11, 2019, issue of Science, told BioWorld another research group has since independently confirmed GABABR1a as the receptor for APP. "But the functional importance was not known. This is the first research to have uncovered the normal function for APP," she said.

The findings suggest that the APP/GABABR1a interaction is an activity-dependent negative feedback mechanism to suppress synaptic release and maintain proper homeostatic control of neural circuits.

The fact that abnormalities such as hyperexcitability and hypersynchronization precede clinical onset of AD, raise the possibility that modulating GABABR1a could represent a route to earlier therapeutic intervention in the disease. There also are studies indicating secreted APP levels are altered in AD patients.

Existing drugs for modulating GABA receptors are nonspecific and have poor side effect profiles. Rice said having narrowed the search for the APP receptor to a specific isoform enhances its attractions as a therapeutic target.

The research also has significance beyond AD, according to co-author Joris de Wit. "Interestingly, GABABR signaling has been implicated in a diverse range of neurological and psychiatric disorders, including epilepsy, depression, addiction and schizophrenia. Now we know how the secreted part of APP modulates neuronal signaling through the receptor, we could develop drugs that restore this type of neuronal signaling in other clinical contexts," he said.