Abstract
Inhibiting the activity of the β-amyloid converting enzyme 1 (BACE1) or reducing levels of BACE1 in vivo decreases the production of amyloid-β. The reticulon family of proteins has four members, RTN1, RTN2, RTN3 and RTN4 (also known as Nogo), the last of which is well known for its role in inhibiting neuritic outgrowth after injury. Here we show that reticulon family members are binding partners of BACE1. In brain, BACE1 mainly colocalizes with RTN3 in neurons, whereas RTN4 is more enriched in oligodendrocytes. An increase in the expression of any reticulon protein substantially reduces the production of Aβ. Conversely, lowering the expression of RTN3 by RNA interference increases the secretion of Aβ, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein. Thus, changes in the expression of reticulon proteins in the human brain are likely to affect cellular amyloid-β and the formation of amyloid plaques.
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References
Vassar, R. et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).
Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537 (1999).
Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).
Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 14, 419–427 (1999).
Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D. & Choe, H. BACE2, a β-secretase homolog, cleaves at the β-site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl. Acad. Sci. USA 97, 9712–9717 (2000).
Yan, R., Munzner, J., Shuck, M. & Bienkowski, M. BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. 276, 34019–34027 (2001).
Bennett, B.D. et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's β-secretase. J. Biol. Chem. 275, 37712–37717 (2000).
Benjannet, S. et al. Post-translational processing of β-secretase (β-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-β production. J. Biol. Chem. 276, 10879–10887 (2001).
Capell, A. et al. Maturation and pro-peptide cleavage of β-secretase. J. Biol. Chem. 275, 30849–30854 (2000).
Pinnix, I. et al. Convertases other than furin cleave β-secretase to its mature form. FASEB J. 15, 1810–1812 (2001).
Yan, R., Han, P., Miao, H., Greengard, P. & Xu, H. The transmembrane domain of the Alzheimer's β-secretase (BACE1) determines its late Golgi localization and access to β-amyloid precursor protein (APP) substrate. J. Biol. Chem. 276, 36788–36796 (2001).
Cai, H. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).
Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).
Roberds, S.L. et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10, 1317–1324 (2001).
Citron, M. Alzheimer's disease: treatments in discovery and development. Nat. Neurosci. 5, 1055–1057 (2002).
Oertle, T. & Schwab, M.E. Nogo and its paRTNers. Trends Cell Biol. 13, 187–194 (2003).
Woolf, C.J. No Nogo: now where to go? Neuron 38, 153–156 (2003).
Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000).
Chen, M.S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).
GrandPré, T., Nakamura, F., Vartanian, T. & Strittmatter, S.M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000).
Bandtlow, C.E. & Schwab, M.E. NI-35/250/Nogo-A: a neurite growth inhibitor restricting structural plasticity and regeneration of nerve fibers in the adult vertebrate CNS. Glia 29, 175–181 (2000).
Moreira, E.F., Jaworski, C.J. & Rodriguez, I.R. Cloning of a novel member of the reticulon gene family (RTN3): gene structure and chromosomal localization to 11q13. Genomics 58, 73–81 (1999).
van de Velde, H.J. et al. NSP-encoded reticulons are neuroendocrine markers of a novel category in human lung cancer diagnosis. Cancer Res. 54, 4769–4776 (1994).
Roebroek, A.J., Contreras, B., Pauli, I.G. & van de Ven, W.J. cDNA cloning, genomic organization, and expression of the human RTN2 gene, a member of a gene family encoding reticulons. Genomics 51, 98–106 (1998).
Huber, A.B., Weinmann, O., Brosamle, C., Oertle, T. & Schwab, M.E. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J. Neurosci. 22, 3553–3567 (2002).
Wang, X. et al. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J. Neurosci. 22, 5505–5515 (2002).
van de Velde, H.J., Roebroek, A.J., Senden, N.H., Ramaekers, F.C. & Van de Ven, W.J. NSP-encoded reticulons, neuroendocrine proteins of a novel gene family associated with membranes of the endoplasmic reticulum. J. Cell Sci. 107, 2403–2416 (1994).
Oertle, T. et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J. Neurosci. 23, 5393–5406 (2003).
Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000).
Francis, R. et al. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell 3, 85–97 (2002).
Kim, S.H., Ikeuchi, T., Yu, C. & Sisodia, S.S. Regulated hyperaccumulation of presenilin-1 and the 'γ-secretase' complex. Evidence for differential intramembranous processing of transmembrane substrates. J. Biol. Chem. 278, 33992–34002 (2003).
Kimberly, W.T. et al. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. USA 100, 6382–6387 (2003).
Takasugi, N. et al. The role of presenilin cofactors in the γ-secretase complex. Nature 422, 438–441 (2003).
Edbauer, D. et al. Reconstitution of γ-secretase activity. Nat. Cell Biol. 5, 486–488 (2003).
Yang, L.B. et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat. Med. 9, 3–4 (2003).
Trapp, B.D., Nishiyama, A., Cheng, D. & Macklin, W. Differentiation and death of premyelinating oligodendrocytes in developing rodent brain. J. Cell Biol. 137, 459–468 (1997).
Acknowledgements
We thank W.R. Mathews and E. Lund for assistance in sample sequencing by MALDI-TOF mass spectroscopy; J. Blaesdale, G. Gill and Q. Shi for discussions; G. Kidd for help with confocal microscopy; and B. Trapp for support and discussion.
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Supplementary information
Supplementary Fig. 1
Tissue distribution of RTN3/Nogo proteins (PDF 66 kb)
Supplementary Fig. 2
Transfected RTN3 does not affect Aβ ratios. (PDF 125 kb)
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He, W., Lu, Y., Qahwash, I. et al. Reticulon family members modulate BACE1 activity and amyloid-β peptide generation. Nat Med 10, 959–965 (2004). https://doi.org/10.1038/nm1088
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DOI: https://doi.org/10.1038/nm1088
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