Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

Abstract

The amyloid precursor protein (APP) is well known to be involved in the pathophysiology of Alzheimer's disease (AD) via its cleavage product amyloid ß (Aß). However, the physiological role of APP, its various proteolytic products and the amyloid precursor-like proteins 1 and 2 (APLP1/2) are still not fully clarified. Interestingly, it has been shown that learning and memory processes represented by functional and structural changes at synapses are altered in different APP and APLP1/2 mouse mutants. In addition, APP and its fragments are implicated in regulating synaptic strength further reinforcing their modulatory role at the synapse. While APLP2 and APP are functionally redundant, the exclusively CNS expressed APLP1, might have individual roles within the synaptic network. The proteolytic product of non-amyloidogenic APP processing, APPsα, emerged as a neurotrophic peptide that facilitates long-term potentiation (LTP) and restores impairments occurring with age. Interestingly, the newly discovered η-secretase cleavage product, An-α acts in the opposite direction, namely decreasing LTP. In this review we summarize recent findings with emphasis on the physiological role of the APP gene family and its proteolytic products on synaptic function and plasticity, especially during processes of hippocampal LTP. Therefore, we focus on literature that provide electrophysiological data by using different mutant mouse strains either lacking full-length or parts of the APP proteins or that utilized secretase inhibitors as well as secreted APP fragments.

Keywords: amyloid precursor protein; amyloid precursor-like protein; long-term potentiation; synaptic plasticity.

Figure 1

Proteolytic processing of APP. Full-length APP can be processed by α-, ß-, η-, and γ-secretases in three different pathways. The left panel illustrates the η-secretase processing of APP. Initially η-secretase cleavage releases the soluble APPsη, while CTFη remains embedded in the membrane. It is further processed by α- or ß-secretase at the extracellular side generating An-α or An-ß. Shedding of CTFη within the transmembrane domain by γ-secretase yields the APP intracellular domain (AICD) containing the highly conserved interaction motif (YENPTY, yellow box) or the short extracellular peptides Aß seen in the amyloidogenic or p3 within the non-amyloidogenic pathway. The non-amyloidogenic pathway depicted in the middle is driven by the α-secretase liberating APPsα in the extracellular space. Subsequently processing of membrane tethered CTFα by γ-secretase generates the p3 peptide and cytoplasmic AICD. The right panel illustrates APP processing in the amyloidogenic pathway by ß-secretase resulting initially in the release of the APPsß ectodomain. Following γ-secretase shedding of the membrane tethered CTFß the Aß peptide is secreted along with AICD in the cytoplasm.

Figure 2

Role of the APP protein family at the synapse. (A) The extracellular domains of APP/APLPs mediate cell-cell adhesion in trans supporting synaptic connectivity. APP and APLP2 are mainly located in the Golgi apparatus and trans Golgi network. When integrated in the plasma membrane, APP and APLP2 show basal adhesive characteristics, while the proportion of plasma membrane APLP1 is higher and it's insertion dynamic. (B) Homodimerized APP might function as a cell-surface G-protein coupled receptor which is recognized by Aß and initiates signaling as well as neurotransmitter release by activation of calcium channels. Aß, Aß1-15, and potential also APPsα induce an AChR-dependent signal facilitating glutamate release via an increase in presynaptic calcium concentration. APP and APLP2 are mainly implicated in presynaptic function and their intracellular domains are associated with proteins of the synaptic vesicle release machinery regulating the vesicle content in the presynaptic active zone. (C) High frequency stimulation increases APP ectodomain shedding that might be linked to the activation of mGluRs or AChRs. High amounts of APPsα facilitate the function of NMDA-Rs by increasing the agonist D-serine or by induction of immediate early genes as well as signaling pathways like that of CamKII to support synaptic plasticity.