TY - JOUR
T1 - Inhibition of α2-macroglobulin/proteinase-mediated degradation of amyloid β peptide by apolipoprotein E and α1-antichymotrypsin
T2 - Evidence that the α2-macroglobulin/proteinase complex mediates degradation of the Aβ peptide
AU - Zhang, Zhiyuan
AU - Drzewiecki, Gary J.
AU - May, Patrick C.
AU - Rydel, Russell E.
AU - Paul, Steven M.
AU - Hyslop, Paul A.
PY - 1996
Y1 - 1996
N2 - The soluble amyloid β-peptide (Aβ), is produced from the amyloid β-protein precursor (AβPP) during normal cellular metabolism. The accumulation and deposition of extracellular Aβ in senile plaques, a characteristic neuropathological feature of Alzheimer's disease (AD), may occur as a result of increased Aβ synthesis or decreased degradation/clearance, or both. We now report that trypsin-activated α2-macroglobulin (α2M-T), efficiently degrades Aβ in vitro. Moreover, incubation of Aβ with α2M-T prevents the in vitro formation of Thioflavine-S positive Aβ fibrils as well as Aβ-induced toxicity of cultured human cortical neuronal (HCN-IA) cells. Two senile plaque-associated proteins, apolipoprotein E (apoE) and α1-antichymotrypsin (ACT), markedly inhibit α2M-T-mediated Aβ degradation by a process that does not involve inhibition of the α2M-T catalytic site. Thus, the degradation and clearance of Aβ by α2M-T may be impaired by the amyloid-promoting factors, apoE and ACT, both of which have been shown to be elevated in AD brain and to be possible genetic risk factors for AD.
AB - The soluble amyloid β-peptide (Aβ), is produced from the amyloid β-protein precursor (AβPP) during normal cellular metabolism. The accumulation and deposition of extracellular Aβ in senile plaques, a characteristic neuropathological feature of Alzheimer's disease (AD), may occur as a result of increased Aβ synthesis or decreased degradation/clearance, or both. We now report that trypsin-activated α2-macroglobulin (α2M-T), efficiently degrades Aβ in vitro. Moreover, incubation of Aβ with α2M-T prevents the in vitro formation of Thioflavine-S positive Aβ fibrils as well as Aβ-induced toxicity of cultured human cortical neuronal (HCN-IA) cells. Two senile plaque-associated proteins, apolipoprotein E (apoE) and α1-antichymotrypsin (ACT), markedly inhibit α2M-T-mediated Aβ degradation by a process that does not involve inhibition of the α2M-T catalytic site. Thus, the degradation and clearance of Aβ by α2M-T may be impaired by the amyloid-promoting factors, apoE and ACT, both of which have been shown to be elevated in AD brain and to be possible genetic risk factors for AD.
KW - Aβ clearance
KW - Proteolytic degradation
KW - α-macroglobulin
UR - http://www.scopus.com/inward/record.url?scp=0000140969&partnerID=8YFLogxK
U2 - 10.3109/13506129609045515
DO - 10.3109/13506129609045515
M3 - Article
AN - SCOPUS:0000140969
SN - 1350-6129
VL - 3
SP - 156
EP - 161
JO - Amyloid
JF - Amyloid
IS - 3
ER -