Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease

Abstract

Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer's disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

Keywords: AMPA receptors; APP; Abeta peptides; Alzheimer’s β-secretase; BACE1; Dopamine receptors; NMDA receptors; Synapses.

Figure 1. Schematic illustration of three types of synapses

Glutamate is an amino acid neurotransmitter and is the primary excitatory neurotransmitter at almost all glutamatergic synapses in the central nervous system. This molecule binds to multiple postsynaptic receptors, including the NMDA receptor (comprising two GluN1 subunits and two GluN2A, 2B, 2C or 2D subunits) and the AMPA receptor (a tetramer formed by two dimers of GluR1, GluR2 or two GluR5 subunits). GluN3 has high affinity for Gly, and it is possible to form a functional NMDA receptor containing GluN1, GluN2 and GluN3. Different combinations of these subunits in NMDA and AMPA receptors exhibit unique synaptic profiles. Synaptic vesicles releasing other neurotransmitters such as acetylcholine for synaptic transmission are not depicted in this figure. GABA is the chief inhibitory neurotransmitter in the central nervous system and plays a principal role in suppressing neuronal excitability throughout the nervous system. It mainly binds to 2 types of postsynaptic GABA receptors, GABA_AR and GABA_BR. GABA_CR are closely related to GABA_AR, although differences in their transmission have been identified but are not listed separately in this figure. GABA_ARs are usually a ligand-gated Cl channel formed by a pentamer, while GABA_BRs belong to the family of seven transmembrane G-coupled protein receptors. Dopamine (DA) is a neurotransmitter of the catecholamine and phenethylamine families that play a number of important roles in cognitive functions including cognitive control, arousal, and motivation. DA mainly binds to D1-like receptors (D1 and D5) and D2-like receptors (D2, D3, and D4).

Figure 2. Soluble Aβ in synaptic dysfunction

Presynaptically expressed APP is cleaved by α-secretase (arrowhead) to release sAPP_α and α-C-terminal fragment (αCTF), which is further cleaved by γ-secretase (blue arrow) to generate P83 and intracellular domain of APP (AICD). APP cleaved by BACE1 (red arrow) releases sAPP_β and βCTF, which is further cleaved by γ-secretase to generate Aβ and AICD. Pathological levels of Aβ are found to interact with NMDA receptors, which are voltage-gated Ca²⁺ channels, and such binding blocks Ca²⁺ flow. AMPA receptors regulate the exchange of Na⁺ or K⁺ via ligand-gated control. The increase in cytosolic Ca²⁺ leads to decreased LTP and increased LTD. In addition to the direct effects on NMDAR and AMPAR proteins, Aβ oligomers are also suggested to form annular amyloid pores, which alter the membrane dielectric barrier and allow influx of Ca²⁺. Aβ oligomers mediate release of glutamate from synaptic vesicles through binding to presynaptic nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs).

Figure 3. Impairments of Aβ on presynaptic and postsynaptic compartments

In Alzheimer’s brains, BACE1 levels are elevated, which will cause production of pathological level of Aβ, in the form of dimers, trimers, or various sizes of oligomers. We summarize the impacts of toxic Aβ on all possible routes based on reports in the literature. Changes in downstream signaling molecules such as PKA and CaMKII in response to disrupted glutamatergic, dopaminergic, and GABAergic synapses are omitted.