Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

Figure 1

A diagram of amyloid precursor protein (APP) processing pathways. The transmembrane protein APP (membrane indicated in blue) can be processed by two pathways, the nonamyloidogenic α-secretase pathway and the amyloidogenic β-secretase pathway. In the nonamyloidogenic pathway, α-secretase cleaves in the middle of the β-amyloid (Aβ) region (red) to release the soluble APP-fragment sAPP-α. The APP C-terminal fragment 83 (APP-CTF83) is then cleaved by γ-secretase to release the APP intracellular domain (AICD) and P3 fragment. In the amyloidogenic pathway, β-secretase cleaves APP to produce the soluble fragment sAPP-β. APP-CTF99 is then cleaved by γ-secretase to produce Aβ ₄₀, Aβ ₄₂ and AICD.

Figure 2

Concentration-dependent effects of Aβ on synaptic function. At normal physiological levels (picomolar range), Aβ peptides have positive effects on synaptic function: they can positively regulate presynaptic release probability and facilitate learning and LTP in CA1 by activating α7-nAChRs. However, when the concentration of Aβ peptides is lower than normal, presynaptic function is impaired. On the other hand, under pathological conditions, such as increased neuronal activity, stress, or the presence of familial Alzheimer's disease (FAD) mutations, the increase in Aβ peptide concentration produces pathological effects, including decreased presynaptic neurotransmitter release, reduced postsynaptic responsiveness, LTP impairment, and LTD facilitation. Therefore, maintaining the concentration of Aβ peptides within a normal physiological range is essential and should be the goal for developing effective treatments for Alzheimer's disease.

Figure 3

The roles of BACE1 in synaptic function. Besides cleaving APP to produce Aβ peptides, BACE1 has been found to have other substrates. It can process the β2 subunit of the voltage-gated sodium (Na⁺) channels, which can regulate Na⁺ channel surface expression and in turn modulate neuronal excitability. In addition, BACE1 can cleave NRG1, which plays a crucial role in myelination and NRG1/ErbB4 signaling. Recently, it has been showed that NRG1 can regulate cell surface expression of α7-nAChRs, which can also affect synaptic transmission.

Figure 4

The roles of presenilins in synaptic function. Two main functions of presenilin 1 (PS1) focused on in this paper are its ability to function as part of the γ-secretase cleavage complex and also to function as an ER Ca²⁺ leak channel. The γ-secretase complex is responsible for the final cleavage of APP in the production of Aβ peptides. The γ-secretase complex has also been shown to regulate spontaneous neurotransmitter release and is crucial for the regulation of the notch signaling pathway especially during early development. The PS1 holoprotein has been proposed to function as an ER Ca²⁺ leak channel. It is responsible for regulating intracellular calcium dynamics and calcium homeostasis required for proper signaling and neurotransmitter release. In addition to these two main functions, knockout studies have shown that the PS1 protein is important for synaptic scaling, proper NMDAR-mediated responses, as well as cell adhesion mediated by N-cadherin. Through these studies it is clear that PS1 plays an important role in synaptic transmission and plasticity.