The most common form of age-associated dementia is Alzheimer's disease (AD). AD afflicts approximately half of adults over 85 years of age, totaling 35.6 million cases of AD worldwide in 2009. While already prevalent, the number of AD cases is estimated to more than double by 2050. Yet, we still do not have a cure for this fatal disease. With its prevalence and devastating effects on not only the patients, but their families as well, and stark lack of effective treatments, we urgently need to develop better therapeutics for AD. Our long-term goal isto delineate molecular pathways of AD pathogenesis in order to identify effective therapeutic strategies that combat AD progression. Recent work revealed that genetic overexpression of klotho, a type-I transmembrane protein, in transgenic mice with a pathogenic form of human amyloid precursor protein, prevented impairments seen in AD, including cognitive decline, loss of dendritic spines, and dysregulation of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B . However, these effects occurred with global overexpression of klotho. As klotho is primarily expressed in the kidney and choroid plexus, this makes the therapeutic feasibility of klotho administration unclear.Moreover, the molecular mechanism(s) by which klotho mediates its effects is unknown. In the periphery, klotho activity has several downstream effectors and is intricately linked to vitamin D metabolism. Yet, we do not know if klotho and these effectors or vitamin D have similar interactions and Here, we propose to answer these unknowns, by testing the 1) peripheral delivery of klotho will enhance cognition and ameliorate pathology in AD model mice; 2) klotho promotes dendritic spines and synaptic expression of GluN2B expression through its sialidase activity and relationships in the brain. hypotheses that: regulation of calcium influx; and 3) vitamin D administration increases klotho expression and function in the brain. To address these hypotheses, we will: determine if delivery of recombinant klotho can enhance learning and memory, dendritic spine density and subtypes, and GluN2B activity and localization by administering klotho to non-transgenic and AD model mice peripherally by subcutaneous pump and into the cerebrospinal fluid by intracerebroventricular infusion; 2) determine the molecular mechanism by which klotho brain. 1) maintains and enhances dendritic spines and regulates GluN2B; 3) determine the relationship between klotho and vitamin D in the brain. Elucidating the underlying molecular mechanisms of AD is essential to developing therapeutics for this widespread and devastating disease. By completing these aims, we could greatly impact the field as this work will provide significant insight into the molecular action of klotho and its feasibility as a therapeutic for AD Even if klotho is not the eventual treatment that succeeds for AD, obtaining such insight into the pathways that cause neuronal dysfunction is critically valuable to identify future candidates and inform future therapeutic manipulations.
Afflicting approximately half of adults over 85 years of age, Alzheimer's disease is the most common form of age-associated dementia. To develop therapeutics for this widespread, devastating, and currently incurable disease, we need to understand the underlying molecular mechanisms that cause dementia in Alzheimer's disease. In this proposal, we will determine if administration of the type-I transmembrane protein klotho is a feasible therapeutic, elucidate the important downstream pathways of klotho's neural functions, and delineate whether vitamin D supplementation and klotho therapeutics can be used together to prevent Alzheimer's disease.
| Zhu, Lei; Stein, Liana R; Kim, Daniel et al. (2018) Klotho controls the brain-immune system interface in the choroid plexus. Proc Natl Acad Sci U S A 115:E11388-E11396 |
| Miyamoto, Takashi; Stein, Liana; Thomas, Reuben et al. (2017) Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture. Mol Neurodegener 12:41 |
