Trends in Pharmacological Sciences
ReviewAPP Receptor? To Be or Not To Be
Section snippets
The Amyloid Precursor Protein
APP is a type 1 transmembrane protein that plays an essential role in Alzheimer's disease (AD). It is the source of cerebral accumulation of β-amyloid peptides (Aβ) which accumulate in brain senile plaques. Cleavage of full-length APP by α- and β-secretases releases the large soluble ectodomain (sAPPα and sAPPβ, respectively), leaving behind membrane-bound C-terminal fragments (CTF) comprising the transmembrane and short cytoplasmic domain (named C83 and C99, respectively) 1, 2. Subsequent
Proteolytic Processing of APP
APP shares similarities in membrane topology and proteolytic processing with several γ-secretase substrates (including Notch and deleted in colorectal carcinoma/DCC) that function as cell surface receptors (Figure 2) 2, 40, 41, 42. The majority of γ-secretase substrates are type I transmembrane proteins, harboring a large ectodomain, a single-pass transmembrane domain, and a cytoplasmic C-terminal domain capable of mediating intracellular signaling. In addition, these substrates are well known
Structural Properties of APP as a Receptor-Like Entity
APP is expressed as three isoforms attributable to tissue-specific alternative splicing (Figure 3A) (reviewed in [13]). The APP695 isoform is predominantly expressed in neurons, whereas the APP751 and APP770 isoforms are expressed in non-neuronal populations. Two mammalian APP homologs, named amyloid precursor-like protein 1 and 2 (APLP-1 and APLP-2), share primary amino acid sequence, structure, and conserved domains with APP (reviewed in 38, 54) (Figure 3A). Although APLP1 and APLP2 undergo
The Role of APP Subdomains in the Dimerization Process
In a manner similar to many type 1 transmembrane domain receptors 44, 69, 70, 71, APP can form homodimers as well as heterodimers by interacting with its homologs or putative ligands. Dimerization of APP is mediated by motifs present in the extracellular and the transmembrane domains of the protein. The extracellular E1 domain at the N-terminal region of APP has been characterized as the major interacting interface for homo- as well as heterodimerization of APP and APLPs at the cell surface 34,
Regulation of APP Cell Surface Localization
Cell surface localization of APP is a prerequisite for APP to fall within the category of receptor-like proteins and molecules involved in cell–cell transdimerization interaction across the membrane. Indeed, a subset of full-length APP (APP-FL) in all cells, including neurons, can be found at the cell surface, where it can interact with putative ligands (below). APP cell surface localization is regulated by a balance between the efficiency of APP secretory trafficking and internalization, and
APP-Mediated Intracellular Signaling
Cell surface receptors initiate intracellular signal transduction in response to extracellular signaling molecules. The idea that APP may behave as a receptor is supported by evidence of signaling associated with APP-CTF or membrane-tethered APP. APP and especially APP-CTF reside in membrane microdomains enriched in cholesterol and sphingolipids (called lipid rafts) 49, 113, 114 that are populated by several cell surface receptors and signaling molecules 115, 116. Raft association of APP would
Secreted APP and Putative Ligand-Induced Signaling
As described above, the N-terminal ectodomain of APP has structural features and molecular domains that enable it to interact with a variety of receptor proteins (Figure 4A). Thus, soluble APP could initiate subsequent signaling upon binding with receptor molecules 2, 12, 65 (Table 1). This concept has emerged from several studies which demonstrated that accumulation or overexpression of APP N-terminal fragments (and in some instances Aβ itself [17]) induced or exacerbated signaling associated
Cross-Interactions of APP and APP Metabolites with Receptor-Like Proteins
APP has been reported to interact with a variety of receptor-like proteins (Table 1). The structural features of APP, which confer its adhesive properties, support the notion that APP and its proteolytic products are capable of initiating molecular interactions that could affect its own signaling or signaling through its interacting partners. Notably, APP (especially its extracellular domain that contains the Aβ sequence) has a preference for interaction with type 1 transmembrane molecules
Functional Consequence of APP Internalization on Aβ Clearance
Receptors are internalized upon ligand binding, which allows the ligand-activated receptor to recruit signaling molecules and efficiently transduce intracellular signaling. In addition, receptor internalization is fundamental to initiate receptor downregulation and desensitization, to promote its clearance from the cell surface, and to further target its own degradation 216, 217, 218. It is a common understanding that GPCRs (and non-GPCRs as well) are rapidly desensitized through receptor
Concluding Remarks
Accumulating evidence strongly supports the idea that APP is not only a molecule that produces toxic Aβ peptides but is also a cell adhesion molecule and a growth factor ligand that can (i) interact with various binding protein partners, (ii) activate signaling pathways, and (iii) elicit physiological responses. Thus, secretase-dependent processing of holo-APP is an excellent way to modulate the levels of cell surface APP receptor and also confer additional cellular roles for APP through the
Acknowledgments
Research in our laboratories is supported by grants from the National Institutes of Health (NS055223, AG046710, and AG042762 to A.T.P.; AG019070 and AG051230 to G.T.), BrightFocus Foundation (A.T.P.), Cure Alzheimer's Fund (G.T.), Illinois Department of Public Health (C.D. and A.T.P.), and Alzheimer's Association (C.D. and A.T.P.). We thank members of our laboratories for helpful discussions.
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