Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease

Arch Neurol. 2002 Sep;59(9):1381-9. doi: 10.1001/archneur.59.9.1381.


Context: Amyloid plaques, a major pathological feature of Alzheimer disease (AD), are composed of an internal fragment of amyloid precursor protein (APP): the 4-kd amyloid-beta protein (Abeta). The metabolic processing of APP that results in Abeta formation requires 2 enzymatic cleavage events, a gamma-secretase cleavage dependent on presenilin, and a beta-secretase cleavage by the aspartyl protease beta-site APP-cleaving enzyme (BACE).

Objective: To test the hypothesis that BACE protein and activity are increased in regions of the brain that develop amyloid plaques in AD.

Methods: We developed an antibody capture system to measure BACE protein level and BACE-specific beta-secretase activity in frontal, temporal, and cerebellar brain homogenates from 61 brains with AD and 33 control brains.

Results: In the brains with AD, BACE activity and protein were significantly increased (P<.001). Enzymatic activity increased by 63% in the temporal neocortex (P =.007) and 13% in the frontal neocortex (P =.003) in brains with AD, but not in the cerebellar cortex. Activity in the temporal neocortex increased with the duration of AD (P =.008) but did not correlate with enzyme-linked immunosorbent assay measures of insoluble Abeta in brains with AD. Protein level was increased by 14% in the frontal cortex of brains with AD (P =.004), with a trend toward a 15% increase in BACE protein in the temporal cortex (P =.07) and no difference in the cerebellar cortex. Immunohistochemical analysis demonstrated that BACE immunoreactivity in the brain was predominantly neuronal and was found in tangle-bearing neurons in AD.

Conclusions: The BACE protein and activity levels are increased in brain regions affected by amyloid deposition and remain increased despite significant neuronal and synaptic loss in AD.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease / enzymology*
  • Amyloid / metabolism
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism
  • Aspartic Acid Endopeptidases / biosynthesis
  • Aspartic Acid Endopeptidases / metabolism*
  • Cerebellar Cortex / metabolism
  • Endopeptidases
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation, Enzymologic / genetics
  • Humans
  • Immunohistochemistry
  • Male
  • Neocortex / enzymology*
  • Plaque, Amyloid / enzymology
  • Precipitin Tests
  • Synaptophysin / metabolism


  • Amyloid
  • Amyloid beta-Peptides
  • Synaptophysin
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human