Background The cleavage of β-amyloid precursor protein (APP) generates multiple proteins: Soluble β-amyloid Precursor Protein Alpha (sAPPα), sAPPβ, and amyloid β (Aβ). Previous studies have shown that sAPPα and sAPPβ possess neurotrophic properties, whereas Aβ is neurotoxic. However, the underlying mechanism of the opposing effects of APP fragments remains poorly understood. In this study, we have investigated the mechanism of sAPPα-mediated neurotrophic effects. sAPPα and sAPPβ interact with p75 neurotrophin receptor (p75NTR), and sAPPα promotes neurite outgrowth. Methods and Findings First, we investigated whether APP fragments interact with p75NTR, because full-length APP and Aβ have been shown to interact with p75NTR in vitro. Both sAPPα and sAPPβ were co-immunoprecipitated with p75NTR and co-localized with p75NTR on COS-7 cells. The binding affinity of sAPPα and sAPPβ for p75NTR was confirmed by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the effect of sAPPα on neurite outgrowth in mouse cortical neurons. Neurite outgrowth was promoted by sAPPα, but sAPPα was uneffective in a knockdown of p75NTR. Conclusion We conclude that p75NTR is the receptor for sAPPα to mediate neurotrophic effects.
References
[1]
Kim D, Tsai LH (2009) Bridging physiology and pathology in AD. Cell 137: 997–1000.
[2]
Salbaum JM, Ruddle FH (1994) Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. J Exp Zool 269: 116–127.
[3]
Guenette S, Chang Y, Hiesberger T, Richardson JA, Eckman CB, et al. (2006) Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development. EMBO J 25: 420–431.
[4]
Hartmann D, De Strooper B, Saftig P (1999) Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr Biol 9: 719–727.
[5]
Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, et al. (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23: 4106–4115.
[6]
Loffler J, Huber G (1992) Beta-amyloid precursor protein isoforms in various rat brain regions and during brain development. J Neurochem 59: 1316–1324.
[7]
Kobayashi S, Sasaki T, Katayama T, Hasegawa T, Nagano A, et al. (2010) Temporal-spatial expression of presenilin 1 and the production of amyloid-beta after acute spinal cord injury in adult rat. Neurochem Int 56: 387–393.
[8]
Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, et al. (2009) Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med 15: 377–379.
[9]
Yoshimura K, Ueno M, Lee S, Nakamura Y, Sato A, et al. (2011) c-Jun N-terminal kinase induces axonal degeneration and limits motor recovery after spinal cord injury in mice. Neurosci Res 71: 266–277.
[10]
Mattson MP (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 77: 1081–1132.
[11]
Corrigan F, Pham CL, Vink R, Blumbergs PC, Masters CL, et al. (2011) The neuroprotective domains of the amyloid precursor protein, in traumatic brain injury, are located in the two growth factor domains. Brain Res 1378: 137–143.
[12]
Siopi E, Cho AH, Homsi S, Croci N, Plotkine M, et al. (2011) Minocycline restores sAPPalpha levels and reduces the late histopathological consequences of traumatic brain injury in mice. J Neurotrauma 28: 2135–2143.
[13]
Thornton E, Vink R, Blumbergs PC, Van Den Heuvel C (2006) Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res 1094: 38–46.
[14]
Dechant G, Barde YA (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci 5: 1131–1136.
[15]
Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10: 381–391.
[16]
Fombonne J, Rabizadeh S, Banwait S, Mehlen P, Bredesen DE (2009) Selective vulnerability in Alzheimer's disease: amyloid precursor protein and p75(NTR) interaction. Ann Neurol 65: 294–303.
[17]
Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, et al. (2009) The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29: 10627–10637.
[18]
Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457: 981–989.
[19]
Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, et al. (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28: 3941–3946.
[20]
Hashimoto Y, Tsukamoto E, Niikura T, Yamagishi Y, Ishizaka M, et al. (2004) Amino- and carboxyl-terminal mutants of presenilin 1 cause neuronal cell death through distinct toxic mechanisms: Study of 27 different presenilin 1 mutants. J Neurosci Res 75: 417–428.
[21]
Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, et al. (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 21: 7551–7560.
[22]
Yaar M, Zhai S, Panova I, Fine RE, Eisenhauer PB, et al. (2007) A cyclic peptide that binds p75(NTR) protects neurones from beta amyloid (1–40)-induced cell death. Neuropathol Appl Neurobiol 33: 533–543.
[23]
Yamashita T, Higuchi H, Tohyama M (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157: 565–570.
[24]
Higuchi H, Yamashita T, Yoshikawa H, Tohyama M (2003) Functional inhibition of the p75 receptor using a small interfering RNA. Biochem Biophys Res Commun 301: 804–809.
[25]
Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, et al. (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16: 543–551.
[26]
Higuchi H, Yamashita T, Yoshikawa H, Tohyama M (2003) PKA phosphorylates the p75 receptor and regulates its localization to lipid rafts. EMBO J 22: 1790–1800.
[27]
Nakazawa H, Sada T, Toriyama M, Tago K, Sugiura T, et al. (2012) Rab33a mediates anterograde vesicular transport for membrane exocytosis and axon outgrowth. J Neurosci 32: 12712–12725.
[28]
Clarris HJ, Cappai R, Heffernan D, Beyreuther K, Masters CL, et al. (1997) Identification of heparin-binding domains in the amyloid precursor protein of Alzheimer's disease by deletion mutagenesis and peptide mapping. J Neurochem 68: 1164–1172.
[29]
Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, et al. (1994) Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14: 5461–5470.
[30]
Ninomiya H, Roch JM, Jin LW, Saitoh T (1994) Secreted form of amyloid beta/A4 protein precursor (APP) binds to two distinct APP binding sites on rat B103 neuron-like cells through two different domains, but only one site is involved in neuritotropic activity. J Neurochem 63: 495–500.
[31]
Small DH, Nurcombe V, Reed G, Clarris H, Moir R, et al. (1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci 14: 2117–2127.
[32]
Chasseigneaux S, Dinc L, Rose C, Chabret C, Coulpier F, et al. (2011) Secreted amyloid precursor protein beta and secreted amyloid precursor protein alpha induce axon outgrowth in vitro through Egr1 signaling pathway. PLoS One 6: e16301.
[33]
Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, et al. (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67: 1882–1896.
[34]
Akar CA, Wallace WC (1998) Amyloid precursor protein modulates the interaction of nerve growth factor with p75 receptor and potentiates its activation of trkA phosphorylation. Brain Res Mol Brain Res 56: 125–132.
[35]
Luo JJ, Wallace MS, Hawver DB, Kusiak JW, Wallace WC (2001) Characterization of the neurotrophic interaction between nerve growth factor and secreted alpha-amyloid precursor protein. J Neurosci Res 63: 410–420.
[36]
Rossner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V (1998) p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. J Neurochem 71: 757–766.
[37]
Wallace WC, Akar CA, Lyons WE (1997) Amyloid precursor protein potentiates the neurotrophic activity of NGF. Brain Res Mol Brain Res 52: 201–212.
[38]
Yamashita T, Tucker KL, Barde YA (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24: 585–593.
[39]
Wang KC, Kim JA, Sivasankaran R, Segal R, He Z (2002) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420: 74–78.
[40]
Yamashita T, Tohyama M (2003) The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat Neurosci 6: 461–467.
[41]
Ben-Zvi A, Ben-Gigi L, Klein H, Behar O (2007) Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning. J Neurosci 27: 13000–13011.
