Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse

Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). However, whether it is a primary cause or merely a downstream consequence in AD pathology is still unknown. We previously generated α-tocopherol transfer protein knockout (Ttpa−/−) mice, in which lipid peroxidation in the brain was significantly increased by complete depletion of α-tocopherol (α-Toc). Here we crossed AD transgenic (APPsw) model mice (Tg2576) with Ttpa−/− mice. The resulting double-mutant (Ttpa−/−APPsw) mice showed earlier and more severe cognitive dysfunction in the Morris water maze, novel-object recognition, and contextual fear conditioning tests. They also showed increased amyloid β-peptide (Aβ) deposits in the brain by immunohistochemical analysis, which was ameliorated with α-Toc supplementation. In this report we provide clear evidence indicating that chronic lipid peroxidation due to α-Toc depletion enhances AD phenotype in a mouse model.