Amyloid Precursor Protein (APP) and GABAergic Neurotransmission

Abstract

The amyloid precursor protein (APP) is the parent polypeptide from which amyloid-beta (Aβ) peptides, key etiological agents of Alzheimer's disease (AD), are generated by sequential proteolytic processing involving β- and γ-secretases. APP mutations underlie familial, early-onset AD, and the involvement of APP in AD pathology has been extensively studied. However, APP has important physiological roles in the mammalian brain, particularly its modulation of synaptic functions and neuronal survival. Recent works have now shown that APP could directly modulate γ-aminobutyric acid (GABA) neurotransmission in two broad ways. Firstly, APP is shown to interact with and modulate the levels and activity of the neuron-specific Potassium-Chloride (K⁺-Cl^-) cotransporter KCC2/SLC12A5. The latter is key to the maintenance of neuronal chloride (Cl^-) levels and the GABA reversal potential (E_GABA), and is therefore important for postsynaptic GABAergic inhibition through the ionotropic GABA_A receptors. Secondly, APP binds to the sushi domain of metabotropic GABA_B receptor 1a (GABA_BR1a). In this regard, APP complexes and is co-transported with GABA_B receptor dimers bearing GABA_BR1a to the axonal presynaptic plasma membrane. On the other hand, secreted (s)APP generated by secretase cleavages could act as a GABA_BR1a-binding ligand that modulates presynaptic vesicle release. The discovery of these novel roles and activities of APP in GABAergic neurotransmission underlies the physiological importance of APP in postnatal brain function.

Keywords: GABA receptor; amyloid precursor protein (APP); amyloid-beta (Aβ); gamma-aminobutyric acid (GABA); potassium chloride cotransporter 2 (KCC2).

Figure 1

A schematic diagram illustrating amyloid precursor protein’s (APP’s) modulation of γ-aminobutyric acid (GABA)ergic neurotransmission via its interaction with potassium chloride cotransporter 2 (KCC2) and GABA_B receptor 1a (GABA_BR1a). A: APP modulates KCC2 expression by suppressing the levels of a KCC2 transcription factor UCF-1 in an unknown manner [65]. B: APP can also interact directly with KCC2, and maintains its levels and stability by inhibiting tyrosine phosphorylation and ubiquitination-based degradation [64]. APP’s modulation of KCC2 levels alters intracellular Cl⁻ and shifts E_GABA, thereby affecting inhibitory signaling through GABA_ARs. C: APP’s interaction with GABA_BR1a’s sushi domain allows it to effectively aid axon targeting of GABA_BR1a-GABA_BR2 dimers [66]. D: Furthermore, secreted (s)APP generated by secretase cleavage could bind as a ligand to GABA_BR1a to modulate GABA_BR’s presynaptic roles [67]. See text for more details.