Iwatsubo, Takeshi

Publication Detail

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Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S.

J S Munger; C Haass; C A Lemere; G P Shi; W S Wong; D B Teplow; D J Selkoe; H A Chapman (Profiled Authors: Selkoe, Dennis J; Haass, Christian; Teplow, David B)

Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
The Biochemical journal 1995;311 ( Pt 1)():299-305.

To investigate the potential contribution of the lysosomal compartment in the processing of amyloid precursor protein (APP) to amyloid beta-peptides (A beta s), we stably overexpressed a series of lysosomal proteases (the cysteine proteases, cathepsins B, L and S, and the aspartic protease, cathepsin D) in a human kidney epithelial cell line (293) transfected to express high levels of beta APP. Preliminary experiments indicated that 293 cells endogenously synthesize cathepsins B, L and D, but not cathepsin S. A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants. E-64d, an inhibitor of lysosomal cysteine proteases, significantly reduced A beta secretion by the cathepsin S transfectants, but had no effect on cells expressing the other proteases. Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion. Immunostaining of human brain sections revealed cathepsin S in cortical neurons and glia in samples of brain from patients with Alzheimer's disease. These results provide evidence in living cells for a pathway in which cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment. This pathway appears to be inducible, distinct from a constitutive pathway used by 293 and other cells to generate A beta, and may be relevant to the pathogenesis of Alzheimer's disease.

2 Originating Grant

• 1.

  SELKOE, DENNIS J

  Aging in the Brain: The Role of the Fibrous Proteins

  1 September 1985 - 30 April 2012

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 6,982,031

• 2.

  SELKOE, DENNIS J

  Aging in the Brain: Role of the Fibrous Proteins

  1 September 1985 - 30 April 2017

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 2,223,247

Scientific Context

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