Amyloid Precursor Protein Trafficking, Processing, and Function

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Jul 25

PMID 18650430

Citations 535

Authors

Gopal Thinakaran

Edward H Koo

Affiliations

Soon will be listed here.

Abstract

Intracellular trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations over the past two decades. APP is the precursor to the amyloid beta-protein (Abeta), the 38-43-amino acid residue peptide that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (AD). Tremendous progress has been made since the initial identification of Abeta as the principal component of brain senile plaques of individuals with AD. Specifically, molecular characterization of the secretases involved in Abeta production has facilitated cell biological investigations on APP processing and advanced efforts to model AD pathogenesis in animal models. This minireview summarizes salient features of APP trafficking and amyloidogenic processing and discusses the putative biological functions of APP.

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References

Selkoe D, Wolfe M . Presenilin: running with scissors in the membrane. Cell. 2007; 131(2):215-21. DOI: 10.1016/j.cell.2007.10.012. View

Riddell D, Christie G, Hussain I, Dingwall C . Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol. 2001; 11(16):1288-93. DOI: 10.1016/s0960-9822(01)00394-3. View

Vetrivel K, Cheng H, Kim S, Chen Y, Barnes N, Parent A . Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem. 2005; 280(27):25892-900. PMC: 1201532. DOI: 10.1074/jbc.M503570200. View

Caille I, Allinquant B, Dupont E, Bouillot C, Langer A, Muller U . Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development. 2004; 131(9):2173-81. DOI: 10.1242/dev.01103. View

Buxbaum J, Thinakaran G, Koliatsos V, OCallahan J, Slunt H, Price D . Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci. 1998; 18(23):9629-37. PMC: 6793291. View

Iwatsubo T . The gamma-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol. 2004; 14(3):379-83. DOI: 10.1016/j.conb.2004.05.010. View

Pietrzik C, Yoon I, Jaeger S, Busse T, Weggen S, Koo E . FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein. J Neurosci. 2004; 24(17):4259-65. PMC: 6729272. DOI: 10.1523/JNEUROSCI.5451-03.2004. View

Cao X, Sudhof T . Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation. J Biol Chem. 2004; 279(23):24601-11. DOI: 10.1074/jbc.M402248200. View

Ghiso J, Rostagno A, Gardella J, Liem L, Gorevic P, Frangione B . A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion. Biochem J. 1992; 288 ( Pt 3):1053-9. PMC: 1131993. DOI: 10.1042/bj2881053. View

10.

Ando K, Iijima K, Elliott J, Kirino Y, Suzuki T . Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J Biol Chem. 2001; 276(43):40353-61. DOI: 10.1074/jbc.M104059200. View

11.

Miller C, McLoughlin D, Lau K, Tennant M, Rogelj B . The X11 proteins, Abeta production and Alzheimer's disease. Trends Neurosci. 2006; 29(5):280-5. DOI: 10.1016/j.tins.2006.03.001. View

12.

Ho A, Sudhof T . Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci U S A. 2004; 101(8):2548-53. PMC: 356987. DOI: 10.1073/pnas.0308655100. View

13.

Kopan R, Ilagan M . Gamma-secretase: proteasome of the membrane?. Nat Rev Mol Cell Biol. 2004; 5(6):499-504. DOI: 10.1038/nrm1406. View

14.

Koo E, Squazzo S . Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994; 269(26):17386-9. View

15.

Liu Q, Zerbinatti C, Zhang J, Hoe H, Wang B, Cole S . Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 2007; 56(1):66-78. PMC: 2045076. DOI: 10.1016/j.neuron.2007.08.008. View

16.

Yang G, Gong Y, Gong K, Jiang W, Kwon E, Wang P . Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett. 2005; 384(1-2):66-71. DOI: 10.1016/j.neulet.2005.04.040. View

17.

Wang B, Yang L, Wang Z, Zheng H . Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc Natl Acad Sci U S A. 2007; 104(35):14140-5. PMC: 1955810. DOI: 10.1073/pnas.0704070104. View

18.

Ma Q, Futagawa T, Yang W, Jiang X, Zeng L, Takeda Y . A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol. 2008; 10(3):283-94. DOI: 10.1038/ncb1690. View

19.

Cao X, Sudhof T . A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001; 293(5527):115-20. DOI: 10.1126/science.1058783. View

20.

Zheng H, Jiang M, Trumbauer M, Sirinathsinghji D, Hopkins R, Smith D . beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995; 81(4):525-31. DOI: 10.1016/0092-8674(95)90073-x. View