Apolipoprotein E alters metabolism of AbetaPP in cells engaged in beta-amyloidosis.
Canine smooth muscle cells (SMCs), cultured from amyloid-affected brain blood vessels accumulate Alzheimer amyloid-beta peptide (Abeta) intracellularly, either spontaneously or after treatment with apolipoprotein E (apoE). ApoE is codeposited with Abeta, which suggests that apoE participates in Abeta accumulation. We tested the hypothesis that apoE-induced accumulation of Abeta in SMCs is caused by an increased production of amyloid-beta precursor protein (AbetaPP) and/or its altered metabolism. We found that 24 hours of treatment with apoE3 or apoE4 induced intracellular accumulation of Abeta-immunoreactive deposits in SMCs but did not influence AbetaPP production and processing. The treatment with apoE3 or E4 for 3 days resulted in the following: increased Abeta-accumulation; reduced levels of secreted Abeta; increased production and cellular retention of mature AbetaPP770; and reduced culture growth, cell proliferation, and viability. ApoE4, but not apoE3, increased cellular levels of mRNA AbetaPP 770 (the main form produced in SMCs) about ninefold. ApoE3 stimulated production and cellular retention of endogenous apoE. We hypothesize that Abeta accumulation is triggered by apoE, which may bind and immobilize soluble Abeta produced in SMCs. The newly formed Abeta deposits may further accelerate Abeta accumulation by altering metabolism of AbetaPP.
Mazur-Kolecka
B
B
New York State Institute for Basic Research in Developmental Disabilities, Department of Pathological Neurobiology, Staten Island 10314, USA.
Frackowiak
J
J
Krzeslowska
J
J
Ramakrishna
N
N
Haske
T
T
Emmerling
M R
MR
Zhang
W
W
Kim
K S
KS
Wisniewski
H M
HM
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000494:pharmacology*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004285:Dogs; D012333:RNA, Messenger / Q000096:biosynthesis
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D012333:RNA, Messenger