Apolipoprotein E alters metabolism of A beta PP in cells engaged in beta-amyloidosis

Canine smooth muscle cells (SMCs), cultured from amyloid affected brain blo od vessels accumulate Alzheimer amyloid-beta peptide (A beta) intracellular ly. either spontaneously or after treatment with apolipoprotein E (apoE). A poE is codeposited with A beta, which suggests that apoE participates in A beta accumulation. We tested the hypothesis that apoE-induced accumulation of A beta in SMCs is caused by an increased production of amyloid-beta prec ursor protein (A beta PP) and/or its altered metabolism. We found that 24 h ours of treatment with apoE3 or apoE4 induced intracellular accumulation of A beta-immunoreactive deposits in SMCs but did not influence A beta PP pro duction and processing. The treatment with apoE3 or E4 for 3 days resulted in the following: increased A beta-accumulation: reduced levels of secreted A beta: increased production and cellular retention of mature A beta PP770 ; and reduced culture growth, cell proliferation, and viability. ApoE4, but not ap6E3. increased cellular levels of mRNA A beta PP 770 (the main form produced in SMCs) about ninefold. ApoE3 stimulated production and cellular retention of endogenous apoE. We hypothesize that A beta accumulation is triggered by apoE, which may bin d and immobilize soluble A beta produced in SMCs. The newly formed A beta d eposits may further accelerate A beta accumulation by altering metabolism o f A beta PP.