O1-03-08: Multiple mechanisms of neuroprotection by cystatin C: Inhibition of Aβ deposition, induction of autophagy, and induction of proliferation

with the FGF receptor required for the binding of FGF23 and maintenance of proper vitamin D signaling. Methods: We used microarray analysis, RT-PCR, Western blotting, siRNAs and enzymatic assays. Results: We performed a gene profile analysis comparing young and old rhesus monkey brains and found Klotho mRNA to be decreased with normal aging. Next, we showed that the Klotho protein decreases with age in rhesus monkey, mouse and rat brain. Klotho is a type I transmembrane protein, and because of its abundance in serum and CSF, we searched for sheddases responsible for its release. We identified ADAM10 and 17 as the Klotho secretases and discovered that insulin activates Klotho secretion. Because of Klotho’s reported antioxidant effects, we measured its levels in the brain tissue of several AD mouse models where markers of oxidation are commonly found. Our results indicate that Klotho expression is lower in the AD models compared to age-matched controls. Conclusions: The anti-aging protein Klotho is decreased in the healthy aged brain and is even further decreased in AD mouse models. Finding ways to increase Klotho expression a protein known to activate antioxidant genes may lead to the design of compounds that will slow the aging process and protect against progressive neurodegenerative diseases such as AD, Parkinson’s disease and amyotrophic lateral sclerosis. Finally, Klotho may provide a link between diabetes and AD.