Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved

Abstract

The pathological implication of amyloid precursor protein (APP) in Alzheimer's disease has been widely documented due to its involvement in the generation of amyloid-β peptide. However, the physiological functions of APP are still poorly understood. APP is considered a multimodal protein due to its role in a wide variety of processes, both in the embryo and in the adult brain. Specifically, APP seems to play a key role in the proliferation, differentiation and maturation of neural stem cells. In addition, APP can be processed through two canonical processing pathways, generating different functionally active fragments: soluble APP-α, soluble APP-β, amyloid-β peptide and the APP intracellular C-terminal domain. These fragments also appear to modulate various functions in neural stem cells, including the processes of proliferation, neurogenesis, gliogenesis or cell death. However, the molecular mechanisms involved in these effects are still unclear. In this review, we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells, as well as the possible signaling pathways that could be implicated in these effects. The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer's disease is essential to advance the understanding of the pathogenesis of Alzheimer's disease, and in the search for potential therapeutic targets.

Keywords: APP; APP intracellular domain; amyloid beta peptide; amyloid precursor protein; neural progenitor cells; neural stem cells; neurogenesis; signaling pathways; soluble APP alpha; soluble APP beta.

Figure 1

Proteolytic processing of APP by non-amyloidogenic pathway and amyloidogenic pathway. In the non-amyloidogenic pathway, APP is sequentially cleaved by α-sec and γ-sec generating sAPPα, p3 and AICD fragments. In the amyloidogenic pathway, APP is sequentially cleaved by β-sec and γ-sec generating sAPPβ, Aβ and AICD fragments. In both cases, the APP processing releases functionally active fragments to the extracellular medium (sAPPα, p3, sAPPβ and Aβ peptide) which seem to modulate or influence several signaling pathways (marked in yellow boxes). Also the release of the intracellular fragment AICD seems to act differently according to its processing pathway. In the non-amyloidogenic pathway, AICD is rapidly degraded, while in the amyloidogenic pathway, AICD acts as a transcriptional regulator of several target genes. APP: Amyloid precursor protein; α-sec: α-secretase; β-sec: β-secretase; γ-sec: γ-secretase; sAPPα: soluble APP-α; sAPPβ: soluble APP-β; AICD: intracellular C-terminal domain; Aβ: amyloid-β; Shh: sonic hedgehog; MAPK: mitogen-activated protein kinase; PI3K/AKT: phosphoinositide 3-kinase/protein kinase B.

Figure 2

Possible implications of APP proteolytic derivatives in Notch signaling, Wnt signaling and Shh signaling. It should be noted that this scheme summarizes some hypotheses about the action exerted by different proteolytic fragments of APP in different signaling pathways, but there is still no clear consensus. (A) In Notch signaling, sAPPα and Aβ peptide could activate the Notch receptor and initiate the signaling cascade that culminates with NICD-mediated transcriptional regulation in the nucleus. (B) The intracellular fragment AICD could act as a transcriptional regulator similar to the NICD fragment, based on their similar routes of generation. In Wnt signaling, Aβ peptide could prevent the interaction of Wnt with its receptor, blocking activation of the signaling cascade. (C) Consequently, GSK3β is not recruited by the receptor and can hyperphosphorylate β-catenin, preventing its translocation to the nucleus and causing its degradation. (D) The intracellular fragment AICD could act as transcriptional regulator of GSK3B, favoring the hyperphosphorylation and degradation of β-catenin mediated by GSK3β. (E) In Shh signaling, a high concentration of Aβ peptide could activate GSK3β (directly or indirectly), which causes the inhibition of Gli transcription factors. (F) The intracellular fragment AICD could act as transcriptional regulator of PTCH1, favoring an increase of Ptch1 receptor thus suppressing the signaling cascade in the absence of Shh ligand. APP: Amyloid precursor protein; γ-sec: γ-secretase; sAPPα: soluble APP-α; AICD: intracellular C-terminal domain; Aβ: amyloid-β; Shh: sonic hedgehog; NICD: Notch intracellular C-terminal domain; GSK3β: glycogen synthase kinase 3β; Smo: smoothened; Ptch1: protein patched homolog 1.