COSMC mutations reduce T-synthase activity in advanced Alzheimer's disease.

INTRODUCTION: Mutations in brain tissues that cumulate with age may contribute to Alzheimer's disease (AD). Abnormal glycoprotein and Tn antigen expression have been demonstrated in AD. We identified C1GALT1C1/COSMC mutations in AD and age-matched normals without AD. The COSMC coding mutations resulted in a significant reduction in T-synthase activity in advanced AD cases. METHODS: Identification of COSMC mutations, Real-Time Quantitative Reverse Transcription PCR (Q-RT-PCR), western blotting, and T-synthase activity assays. RESULTS: COSMC mutations were detected in the promotor, coding region and 3'UTR in AD and normals. COSMC coding mutations demonstrated a correlation with AD progression. T-synthase levels were significantly elevated in advanced AD compared to AD III (P = 0.03) and normals (P = 0.002). T-synthase activity in advanced AD {Braak and Braak (B&B) stages V and VI} with COSMC coding mutations was 3-fold lower than advanced AD without mutations, and 1.3-fold lower than normal (P = 0.001) and AD B&B stage III (P = 0.01) with coding mutations. DISCUSSION: COSMC coding mutations significantly diminished T-synthase activity in advanced AD, potentially causing defective galactosylation.