Protective effects of a small-molecule inhibitor DDQ against tau-induced toxicities in a transgenic tau mouse model of Alzheimer's disease.

The purpose of our study is to determine, DDQ (diethyl (3,4-dihydroxyphenethylamino) (quinolin-4-yl) methylphosphonate) is a newly discovered molecule that has been shown to protect against phosphorylated tau (p-tau) in Alzheimer's disease (ad) pathogenesis. We used a well-studied tau (P301L) transgenic mouse model to achieve our goal. We administered DDQ, into 12-month-old Tau mice, at 20 mg/kg body weight intraperitoneally two times per week for two months. We also assessed DDQ levels in the blood, skeletal muscle, and brain using biochemical and molecular techniques. We investigated the mRNA and protein levels of mitochondrial dynamics, biogenesis, synaptic, p-tau, and longevity genes sirtuins in DDQ-treated tau mice using real time quantitative PCR (q-RT-PCR), immunoblotting, and immunofluorescence techniques. Our extensive pharmacodynamics investigations revealed that skeletal muscle had the greatest peak levels of DDQ, followed by serum and brain. Interestingly, DDQ-treated tau mice had higher levels of mitochondrial fusion, biogenesis, synaptic genes, and sirtuins than DDQ-untreated tau mice. In addition, DDQ-treated tau mice had lower levels of mitochondrial fission and p-tau than untreated tau mice. The current findings, combined with our prior findings, firmly show that DDQ possesses anti-aging, anti-amyloid-beta, and anti-p-tau properties, making it a promising molecule for reducing age-related, amyloid-beta, and p-tau-induced synaptic and mitochondrial toxicities in Alzheimer's disease.