12 September 2002. 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
Fukumoto H, Cheung BS, Hyman BT, and Irizarry MC. β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 2002 September 12;59:1367-1368. (Abstract)
Rosenberg R. Explaining the cause of the amyloid burden in Alzheimer disease. Arch. Neurol. 2002 September 12;59:1367-1368 (Abstract)