The effect of oxidative stress on amyloid precursor protein processing in cells engaged in ?-amyloidosis is related to apolipoprotein E genotype

Abstract

The reduced antioxidative defense in allele epsilon4 carriers is suggested to contribute to beta-amyloidosis in Alzheimer's disease and Down's syndrome. We studied the effect of oxidative stress on accumulation of amyloid-beta peptide (Abeta) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-beta in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Abeta-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in epsilon4 carriers. Here, we demonstrate that ferrous ions induce formation of Abeta deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular beta-amyloidosis. Cellular accumulation of Abeta in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in epsilon4/epsilon4 than in epsilon3/epsilon3 myocytes and reduced the amount of soluble APPalpha in epsilon3/epsilon3, but not epsilon4/epsilon4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in epsilon3/epsilon3, but not epsilon4/epsilon4, cells. C-terminal APP-immunoreactive material was accumulated in lysosomes partly with Abeta- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Abeta, particularly in epsilon4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Abeta and contribute to the increased risk of development of beta-amyloidosis in epsilon4/epsilon4 carriers.

Association between enzymatic and non-enzymatic antioxidant defense mechanism with apolipoprotein E genotypes in Alzheimer disease

“…This has prompted a search for other factors that may confer susceptibility to AD. Recent findings indicate that cellular events involving oxidative stress may be a basic mechanism for neurodegenerative disease such as AD [1,3,[7][8][9][10][11][12][13][14][15].…”

“…Glutathione peroxidase (GSH-Px) and catalase (CAT) will then convert H 2 O 2 to a water molecule. Cu-Zn SOD, GSH-Px and CAT together provide the primary antioxidant defense mechanism [2,7,8,[11][12][13]16,17].…”

“…There is a balance between both the activity and intracellular levels of these antioxidants that are essential for the survival of organisms and their health [4,8,[11][12][13]16]. It is known that the brain bears relatively low antioxidant protection and also contains high levels of polyunsaturated fatty acids that make it prone to increased lipid peroxidation [2,18].…”

“…Recent studies also indicate that amyloid beta-peptide (Aβ) may be neurotoxin by mechanisms involving the generation of H 2 O 2 , reactive oxygen species (ROS) and lipid peroxidation. β amyloid toxicity is eliminated by free radical scavengers [11][12][13]19]. Researchers have shown conflicting results that APOE at physiological level has isoforms specific effect in protecting neuronal cells from free radicals and oxidative cell death [11,16,18,20].…”

“…Researchers have shown conflicting results that APOE at physiological level has isoforms specific effect in protecting neuronal cells from free radicals and oxidative cell death [11,16,18,20]. These effects correlated with in vitro APOE antioxidant activity (ranked E2 N E3 N E4) [3,12,14,18,[21][22][23]. The three ApoE isoforms are ApoE2, ApoE3, and ApoE4 corresponding to APOE-ɛ2, APOE-ɛ3 and APOE-ɛ4 alleles, respectively [1,6,18].…”