Apical sorting of beta-secretase limits amyloid beta-peptide production - PubMed (original) (raw)

. 2002 Feb 15;277(7):5637-43.

doi: 10.1074/jbc.M109119200. Epub 2001 Dec 6.

Affiliations

• PMID: 11741885
• DOI: 10.1074/jbc.M109119200

Free article

Apical sorting of beta-secretase limits amyloid beta-peptide production

Anja Capell et al. J Biol Chem. 2002.

Free article

Abstract

Polarized cells such as neurons and endothelial cells appear to be involved in two invariant pathological features of Alzheimer's disease pathology, namely the formation of senile plaques and cerebral amyloid angiopathy. This implicates polarized sorting mechanisms in the production and accumulation of amyloid beta-peptide (Abeta). We have now studied polarized sorting of beta-secretase (BACE) in Madin-Darby canine kidney (MDCK) cells. The majority of BACE is sorted to the apical surface of MDCK cells where very little beta-amyloid precursor protein (betaAPP) is observed, because betaAPP undergoes basolateral sorting. Consistent with the usage of similar mechanisms for polarized sorting, BACE was also found to be targeted to axons of hippocampal neurons. The remaining basolaterally sorted BACE competes with the highly polarized basolateral alpha-secretase activity. Therefore, substantial amounts of BACE are targeted away from betaAPP to a non-amyloidogenic compartment, a cellular mechanism that limits Abeta generation. In addition, no alpha-secretase activity was observed on the apical side whereas gamma-secretase activity is observed on the basolateral and the apical side. Consistent with this finding, substantial amounts of Abeta can be produced apically upon missorting of betaAPP to the apical surface. These data demonstrate that Abeta production is limited in polarized cells by differential targeting of BACE and its substrate betaAPP. Moreover, our findings suggest that betaAPP may not be a major physiological substrate of BACE.

PubMed Disclaimer

Similar articles

• Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity.
  Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ. Shi XP, et al. J Biol Chem. 2003 Jun 6;278(23):21286-94. doi: 10.1074/jbc.M209859200. Epub 2003 Mar 27. J Biol Chem. 2003. PMID: 12665519
• A non-amyloidogenic function of BACE-2 in the secretory pathway.
  Fluhrer R, Capell A, Westmeyer G, Willem M, Hartung B, Condron MM, Teplow DB, Haass C, Walter J. Fluhrer R, et al. J Neurochem. 2002 Jun;81(5):1011-20. doi: 10.1046/j.1471-4159.2002.00908.x. J Neurochem. 2002. PMID: 12065613
• Retromer regulates postendocytic sorting of β-secretase in polarized Madin-Darby canine kidney cells.
  Cuartero Y, Mellado M, Capell A, Alvarez-Dolado M, Verges M. Cuartero Y, et al. Traffic. 2012 Oct;13(10):1393-410. doi: 10.1111/j.1600-0854.2012.01392.x. Epub 2012 Jul 25. Traffic. 2012. PMID: 22758778
• Genes and mechanisms involved in beta-amyloid generation and Alzheimer's disease.
  Steiner H, Capell A, Leimer U, Haass C. Steiner H, et al. Eur Arch Psychiatry Clin Neurosci. 1999;249(6):266-70. doi: 10.1007/s004060050098. Eur Arch Psychiatry Clin Neurosci. 1999. PMID: 10653281 Review.
• Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?
  Nawrot B. Nawrot B. Acta Biochim Pol. 2004;51(2):431-44. Acta Biochim Pol. 2004. PMID: 15218540 Review.

Cited by

• Alzheimer's disease beta-amyloid peptides are released in association with exosomes.
  Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. Rajendran L, et al. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7. doi: 10.1073/pnas.0603838103. Epub 2006 Jul 12. Proc Natl Acad Sci U S A. 2006. PMID: 16837572 Free PMC article.
• The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer's Disease.
  Cole SL, Vassar R. Cole SL, et al. Curr Genomics. 2007 Dec;8(8):509-30. doi: 10.2174/138920207783769512. Curr Genomics. 2007. PMID: 19415126 Free PMC article.
• Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
  Mitterreiter S, Page RM, Kamp F, Hopson J, Winkler E, Ha HR, Hamid R, Herms J, Mayer TU, Nelson DJ, Steiner H, Stahl T, Zeitschel U, Rossner S, Haass C, Lichtenthaler SF. Mitterreiter S, et al. J Neurosci. 2010 Jun 30;30(26):8974-83. doi: 10.1523/JNEUROSCI.1199-10.2010. J Neurosci. 2010. PMID: 20592218 Free PMC article.
• Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer's Disease.
  Bhattacharya A, Izzo A, Mollo N, Napolitano F, Limone A, Margheri F, Mocali A, Minopoli G, Lo Bianco A, Di Maggio F, D'Argenio V, Montuori N, Lavecchia A, Sarnataro D. Bhattacharya A, et al. J Pers Med. 2020 Nov 16;10(4):232. doi: 10.3390/jpm10040232. J Pers Med. 2020. PMID: 33207563 Free PMC article.
• Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis.
  Small SA, Gandy S. Small SA, et al. Neuron. 2006 Oct 5;52(1):15-31. doi: 10.1016/j.neuron.2006.09.001. Neuron. 2006. PMID: 17015224 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science
  • eScholarship, California Digital Library, University of California

• Other Literature Sources

  • The Lens - Patent Citations Database