BACE Above Base in Alzheimer’s Patients

Amyloid-β, the peptide that makes up the interneural plaques found in the brains of Alzheimer’s disease patients, is produced by proteolytic processing at the N-terminal of the much larger Aβ precursor protein (AβPP). Though the exact reason for plaque formation remains elusive it could be simply explained by either enhanced production, or depressed degradation and clearance, of the peptide. Two proteases are required for the enzymatic topping and tailing that generates Aβ, and data to be published tomorrow in Archives of Neurology suggests that elevated levels of one of them, the β-site Aβ cleaving enzyme, or BACE, may contribute to the etiology of Alzheimer’s disease.

Researchers working in Michael Irizarry’s lab at Massachusetts General Hospital, Charlestown, examined post-mortem tissue from the brains of Alzheimer’s patients and age-matched controls. First author Hiroaki Fukumoto and colleagues found that, compared to controls, protein concentrations of BACE in AD patients were 14 percent higher in the temporal cortex, a region known to accumulate plaques. In contrast, no differences were found between BACE levels in the cerebellar cortex, which remains relatively plaque free.

This work supports data published earlier this year by Holsinger et al , who used Western blotting to show that BACE protein levels are elevated in AD cortex. Fukumoto et al. took the measurements a step further by designing an assay that measures the proteolytic activity of BACE. This assay revealed that BACE activity is elevated by over 60 percent in the temporal cortex and by 13 percent in the frontal cortex. Furthermore, the activity-to-protein ratio was elevated by 45 percent in the temporal cortex, indicating that the proteolytic activity can be modulated post-translationally, a factor that may be important in AD pathogenesis.

Editor Roger Rosenberg, University of Texas Southwestern Medical Center, Dallas, points out in an accompanying commentary that neither the authors nor Holsinger et al, found increases in Aβ commensurate with their BACE findings. Nevertheless, Rosenberg suggests that this evidence should spur on the search for a BACE inhibitor that could prevent or halt the progression of AD.—Tom Fagan

Comments

  1. This manuscript is very similar to ours, which we submitted to a major journal, where it has been held for more than 9 months! Anyway, the results are very interesting. They are consistent with and support our recent discovery made in collaboration with Martin Citron of Amgen, Riqian Yan of Pharmacia, Weiming Xia of the Center for Neurologic Diseases at Harvard Medical School, and Philip Wong and Don Price from Johns Hopkins University. This past February, we reported these findings at a Keystone symposium.

    We used our recently developed BACE ELISA to detect significantly elevated BACE levels in our rapidly autopsied brain tissues (i.e. within 3 hours) from Alzheimer's disease patients. Not only that, we also found BACE activity is increased in those sporadic AD brains. Lastly, we found the BACE product, C99, is increased in AD brains compared to non-demented brains. This finding suggests that elevated BACE cleavage of AβPP may be one of the mechanisms that lead to enhanced deposition of amyloid plaques found in brains of sporadic AD patients. Now the question is why BACE is elevated in AD brains. Our groups and many other laboratories are actively working in this direction to see if we will be able to regulate BACE expression and activity in the brain so that we might provide clues for drug discovery.

    View all comments by Yong Shen

  2. I highly recommend this article BUT suggest readers to supplement unipolar viewpoint of Archives of Neurology Editor-in-Chief: Alzheimer's disease and amyloid beta protein Koudinov AR et al. Science online, Published 25 June 2002; Amyloid hypothesis: summer 2002 and 8th International Conference on Alzheimer’s disease update. Koudinov and Koudinova BMJ 31 July 2002; The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Rottkamp CA et al., 2002; Alzheimer's disease and amyloid beta protein: a dogma is bad for science. Koudinov AR et al. 32nd SFN Annual Meeting November 2-7, 2002 [Abstracts].

    References:

    Rottkamp CA, Atwood CS, Joseph JA, Nunomura A, Perry G, Smith MA. The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides. 2002 Jul;23(7):1333-41. PubMed.

    View all comments by Alexei Koudinov

  3. I recommend this article as well as the following related contribution: Alzheimer's disease and amyloid beta protein Koudinov AR et al. Science online, Published 25 June 2002; Amyloid hypothesis: summer 2002 and 8th International Conference on Alzheimer’s disease update. Koudinov and Koudinova BMJ 31 July 2002; The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Rottkamp CA et al., 2002; Alzheimer's disease and amyloid beta protein: a dogma is bad for science Koudinov AR et al. 32nd SFN Annual Meeting November 2-7, 2002 [Abstracts].

    References:

    Rottkamp CA, Atwood CS, Joseph JA, Nunomura A, Perry G, Smith MA. The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides. 2002 Jul;23(7):1333-41. PubMed.

    View all comments by Alexei Koudinov

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References

Paper Citations

  1. Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol. 2002 Jun;51(6):783-6. PubMed.

Further Reading

Primary Papers

  1. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002 Sep;59(9):1381-9. PubMed.
  2. Rosenberg RN. Explaining the cause of the amyloid burden in Alzheimer disease. Arch Neurol. 2002 Sep;59(9):1367-8. PubMed.

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