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 (EGABA), and is therefore important for postsynaptic GABAergic inhibition through the ionotropic GABAA receptors. Secondly, APP binds to the sushi domain of metabotropic GABAB receptor 1a (GABABR1a). In this regard, APP complexes and is co-transported with GABAB receptor dimers bearing GABABR1a to the axonal presynaptic plasma membrane. On the other hand, secreted (s)APP generated by secretase cleavages could act as a GABABR1a-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.
Highlights
Alzheimer’s disease (AD) [1] is the most prevalent cause for aging-associated dementia [2]
It is clear that proteolytic processing of amyloid precursor protein (APP) is complex [6,7,8,9] and no clinical trial of anti-Aβ drugs have shown any clear benefits to date [10], Aβ remains a prime AD
In a mouse model of Down syndrome (DS), with mice harboring an extra chromosome 16 on which APP is located, GABAA receptors (GABAA R) signaling was found to be excitatory rather than inhibitory in hippocampal slices from the DS mice [76]. This appears to be associated with an increase in hippocampal Na+ -K+ -2Cl− cotransporter 1 (NKCC1) expression and an inhibition of NKCC1 activity was able to reverse the phenotype
Summary
Alzheimer’s disease (AD) [1] is the most prevalent cause for aging-associated dementia [2]. Fairly ubiquitous in its expression, a good number of physiological roles for APP and its non-amyloid cleavage products are known to affect neurons and neurotransmission. GABA is mainly hyperpolarizing and inhibitory, but it is primarily depolarizing and excitatory in developing neurons, as demonstrated using rat embryonic and neonatal cortical slices [59]. In a mouse model of Down syndrome (DS), with mice harboring an extra chromosome 16 on which APP is located, GABAA R signaling was found to be excitatory rather than inhibitory in hippocampal slices from the DS mice [76] This appears to be associated with an increase in hippocampal NKCC1 expression and an inhibition of NKCC1 activity was able to reverse the phenotype. New findings on how APP influences this shift are discussed
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