TY - JOUR
T1 - Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells
T2 - Evidence that cleavage at the "β-secretase" site occurs in the Golgi apparatus
AU - Thinakaran, Gopal
AU - Teplow, David B.
AU - Siman, Robert
AU - Greenberg, Barry
AU - Sisodiat, Sangram S.
PY - 1996/4/19
Y1 - 1996/4/19
N2 - The 4-kDa β-amyloid peptide (Aβ), a principal component of parenchymal amyloid deposits in Alzheimer's disease, is derived from amyloid precursor proteins (APP). To identify potential intracellular compartments involved in Aβ production, we expressed human APP-695 (APPwt) and APP-695 harboring the Swedish double mutation (APPswe) associated with familial early-onset Alzheimer's disease, in mouse N2a cells. We demonstrate that cells expressing APPswe secrete high levels of Aβ peptides and β-secretase-generated soluble APP derivatives (APPsβ) relative to cells expressing APPwt. In addition, we observed a concomitant diminution in the levels of α-secretase-generated soluble APP derivatives (APPsα). Our interpretation of these findings is that β-secretase cleavage occurs in an intracellular compartment and disables those substrates which would normally be cleaved by α-secretase. As anticipated, the levels of APPswe are diminished relative to the steadystate levels of surface-bound APPwt; moreover, surface-bound APPswe and APPwt molecules are released from the plasma membrane after cleavage by α-secretase, but not by β-secretase. Finally, by examining the rate of appearance of specific APP metabolites generated by β-secretase, we now unequivocally demonstrate that β-secretase cleavage of APPswe occurs within the Golgi apparatus, as early as the medial compartment.
AB - The 4-kDa β-amyloid peptide (Aβ), a principal component of parenchymal amyloid deposits in Alzheimer's disease, is derived from amyloid precursor proteins (APP). To identify potential intracellular compartments involved in Aβ production, we expressed human APP-695 (APPwt) and APP-695 harboring the Swedish double mutation (APPswe) associated with familial early-onset Alzheimer's disease, in mouse N2a cells. We demonstrate that cells expressing APPswe secrete high levels of Aβ peptides and β-secretase-generated soluble APP derivatives (APPsβ) relative to cells expressing APPwt. In addition, we observed a concomitant diminution in the levels of α-secretase-generated soluble APP derivatives (APPsα). Our interpretation of these findings is that β-secretase cleavage occurs in an intracellular compartment and disables those substrates which would normally be cleaved by α-secretase. As anticipated, the levels of APPswe are diminished relative to the steadystate levels of surface-bound APPwt; moreover, surface-bound APPswe and APPwt molecules are released from the plasma membrane after cleavage by α-secretase, but not by β-secretase. Finally, by examining the rate of appearance of specific APP metabolites generated by β-secretase, we now unequivocally demonstrate that β-secretase cleavage of APPswe occurs within the Golgi apparatus, as early as the medial compartment.
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U2 - 10.1074/jbc.271.16.9390
DO - 10.1074/jbc.271.16.9390
M3 - Article
C2 - 8621605
AN - SCOPUS:0029942495
VL - 271
SP - 9390
EP - 9397
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 16
ER -