Cycle on Wheels: Is APP Key to the AppBp1 Pathway?

Review Article

Austin Alzheimers J Parkinsons Dis. 2014;1(2): 7.

Cycle on Wheels: Is APP Key to the AppBp1 Pathway?

Chen Y1,2*, Neve RN4, Zheng H3, Griffin WST1,2, Barger SW1,2 and Mrak RE5

1Department of Geriatrics, University of Arkansas for Medical Sciences, USA

2Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, USA

3Huffington Center on Aging, Baylor College of Medicine, USA

44Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, USA

5Department of Pathology, University of Toledo Health Sciences Campus, USA

*Corresponding author: Chen Y, Department of Geriatrics and Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Received: September 02, 2014; Accepted: September 29, 2014; Published: September 30, 2014


Alzheimer’s disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. The AppBp1 pathway, also known as the neddylation pathway, activates the small ubiquitin-like protein nedd8, which covalently modifies and switches on Cullin ubiquitin ligases, which are essential in the turnover of cell cycle proteins. Here we discuss how APP may activate the AppBp1 pathway, which downregulates cell cycle markers and protects genome integrity. More investigation of this mechanism-driven hypothesis may provide insights into disease treatment and prevention strategies.

Keywords: APP; Alzheimer’s disease; Ubiquitination; Neddylation; Cell cycle


APP: Amyloid Precursor Protein; AICD: APP Intracellular Domain; Aβ: β-Amyloid; NAE: Nedd8 Activating Enzyme, i.e. AppBp1 and Uba3 heterodimer; CCM: Cell Cycle Marker; C57: APP’s C-Terminal 57 amino acids; AppBp1: APP-Binding Protein-1, also known as APP-BP1 or NAE1; DDB1: UV-Damaged, DNA-Binding protein 1; DCAF: DDB1-Cul4-associated factor


The Amyloid Precursor Protein (APP) is central to understanding Alzheimer’s disease (AD) pathogenesis due to its genetic, biochemical and neuropathological connections with AD. First, APP is the source of β-amyloid (Aβ), a major component of senile plaques in AD brains. Secondly, Genetic mutations of APP cause familial AD [1,2]. Furthermore, an increase in APP gene dosage also causes Aβ deposition and related dementia [3-5]. In the case of trisomy of chromosome 21, AD neuropathology develops universally due to an extra copy of APP [6]. Therefore, elucidating the function of APP may give insights into disease prevention and treatment strategies.

APP is a Type-1 transmembrane receptor [7-10], which is cleaved by multiple proteases. Sequential cleavage by β-secretase BACE1 at the extra-cellular domain [11-13] followed by γ-secretase cleavage inside the membrane [14-16] generates secreted APP N-terminal fragment sAPPβ, Aβ peptides of various length, and APP intracellular domain (AICD) [17-19]. Alternatively, cleavage of APP by the α-secretase within the Aβ domain [20,21] followed by γ-secretase cleavage generates sAPPα, p3, and AICD. Despite intensive studies of APP [22-24] and its cleavage products, the function of APP remains poorly understood.

Molecular basis for APP in cell cycle regulation

In an effort to understand APP as a potential signaling receptor,at least 18 proteins have been identified to bind AICD [25-27]. Among them is APP-binding protein-1 (AppBp1), which binds APP’s C-terminal 57 amino acids (C57) [28]. Co-immunoprecipitation experiments further defined AppBp1’s binding site to two segments of C57: one is adjacent to the membrane including three lysine residues and the other in the C-terminal 31 amino acids [29,30] (Figure 1A). The function of AppBp1 was unknown when it was cloned as an APPbinding protein. The significance of the interaction emerged when AppBp1 was discovered as a cell cycle protein. The first evidence was obtained from hamster ts41 cells, which harbor a temperaturesensitive mutant of AppBp1’s homologue, ts41 [31,32]. At the nonpermissive temperature of 40oC, ts41 cells undergo apoptosis after successive DNA synthesis without cell division [32]. Transfection of the human homologue AppBp1 into ts41 cells restores normal cell cycle at the non-permissive temperature [33]. These data establish AppBp1 as a key player in cell cycle progression across the S-M checkpoint.

The cell cycle is tightly regulated by ubiquitination through an enzymatic cascade that transfers ubiquitin to selected proteins for proteasomal degradation. The first clue to the function of AppBp1 in the cell cycle is that it is highly homologous to the N-terminus of the ubiquitin-activating enzyme Uba1 [28] (Figure 1B). However, AppBp1 lacks the C-terminal conserved cysteine residue necessary for the formation of a thioester bond with ubiquitin [28,34]. AppBp1 was soon shown to bind Uba3, which is highly homologous to the C-terminus of Uba1 and has the corresponding active site cysteine [35,36] (Figure 1B). Together, AppBp1 and Uba3 form a bipartite Nedd8 Activating Enzyme (NAE) for the ubiquitin-like protein nedd8 (see reviews [37,38]). In the enzymatic cascade that activates nedd8, AppBp1 is upstream of Uba3 since Uba3 is not able to restore ts41 cell growth when AppBp1 is inactivated by non-permissive temperature [33]. Mutation of Uba3 in C. elegans also profoundly affects mitosis, presumably by affecting the same nedd8-activation pathway [39].