All in the Family: How the APPs Regulate Neurogenesis

Abstract

Recent intriguing evidence suggests that metabolites of amyloid precursor protein (APP), mutated in familial forms of Alzheimer's disease (AD), play critical roles in developmental and postnatal neurogenesis. Of note is soluble APPα (sAPPα) that regulates neural progenitor cell proliferation. The APP family encompasses a group of ubiquitously expressed and evolutionarily conserved, type I transmembrane glycoproteins, whose functions have yet to be fully elucidated. APP can undergo proteolytic cleavage by mutually exclusive pathways. The subtle structural differences between metabolites generated in the different pathways, as well as their equilibrium, may be crucial for neuronal function. The implications of this new body of evidence are significant. Miscleavage of APP would readily impact developmental and postnatal neurogenesis, which might contribute to cognitive deficits characterizing Alzheimer's disease. This review will discuss the implications of the role of the APP family in neurogenesis for neuronal development, cognitive function, and brain disorders that compromise learning and memory, such as AD.

Keywords: Alzheimer’s disease; aging; amyloid precursor protein; learning and memory; neurogenesis; neuronal plasticity.

Figure 1

APP structure. APP contains many functional domains as illustrated. The three most abundant isoforms of APP are APP₇₇₀, APP₇₅₁, and the predominantly neuronal APP₆₉₅. From the N-terminal region these domains include a heparin binding and growth factor like domain (HBD1/GFLD), a copper binding domain (CuBD), zinc binding domain (ZnBD), an acidic region (DE), Kunitz-type protease inhibitor domain (KPI; not present in APP₆₉₅), a second heparin binding domain (HBD2), random coiled region (RC), and the amyloid beta domain (Aβ). The inset displays the human amyloid beta sequence in red along with the sites of APP cleavage by α-, β-, and γ-secretase.

Figure 2

APP processing: similarities to Notch processing. Both APP and Notch receptor may undergo proteolytic cleavage by α-secretase. In the case of APP, this cleavage prevents the formation of beta-amyloid (Aβ) peptides, and induces the release of the p3 fragment and the retention of a membrane-tethered fragment [carboxyl-terminal fragments of APP (APP-CTFs)], that is a substrate of γ-secretase cleavage, yielding APP intracellular domain (AICD) fragments. In the alternative, amyloidogenic pathway, APP is cleaved by β-secretase prior to γ-secretase. In the case of the Notch receptor, the holoprotein is cleaved in the trans Golgi network by a furin-like protease activity in the juxtamembrane extracellular domain, giving rise to two fragments (120 and 180 kDa) that remain associated as a heterodimer. It is thought that Notch reaches the cell membrane in this assembly, where it can undergo activation by ligand binding, following which it gets cleaved by α-secretase to yield the “Notch extracellular truncated” derivative (NEXT). Similarly to the APP-CTFs, only this truncated derivative is then cleaved by γ-secretase. Similarly to NICD, AICD fragments are thought to translocate to the nucleus and activate gene transcription.

Figure 3

APP metabolites in neurogenesis. The formation of new neurons or astroglia in the adult brain is a multifaceted process including the necessity of a niche that supports continuous proliferation of neural progenitor cells, the determination of neural lineage, migration of immature cells often across large distances, and the functional incorporation into existing neural networks. Many of the metabolites of APP have been implicated in one or more of these processes. In order to fully understand the impact of APP metabolism on neurogenic processes, we must first unravel the individual functions of each of the metabolites in order to better realize the implications of alterations in the cleavage pattern of APP.