With the rapid increase in the world's aging population, a cure for neurodegenerative conditions is urgently needed. Alzheimer's disease (AD), the most common disease of memory in the elderly, devastates the minds of millions of people every year. Research over the past decade has revealed that amyloid- (A ) peptides, soluble toxins, play a central role in the pathogenesis of AD. However, despite our growing knowledge of how AD devastates the brain, there are no effective treatments to prevent or modify the course of the disease. This proposal is aimed at identifying and developing neuroprotective strategies against AD. We propose to investigate novel functions of collagen VI, an extracellular matrix protein, in protection against the deleterious effects of A in the brain. Our preliminary studies show that collagen VI, which is robustly increased in the brain in a mouse model of AD and in human AD, dramatically prevents the toxicity of A in mouse neurons. To extend these findings, in Specific Aim 1, we will examine the extracellular actions of collagen VI, with the goal of determining whether collagen VI binds A , alters its assembly, and enhances amyloid plaque formation.
In Specific Aim 2, we will investigate intracellular mechanisms of collagen VI- mediated protection to determine whether collagen VI alters the expression of key survival factors to counter A toxicity.
In Specific Aim 3, we will focus on the effects of collagen VI on behavior and ascertain whether collagen VI prevents A -dependent cognitive dysfunction. Our studies may reveal key protective mechanisms that could serve as direct targets for the development of treatments for AD and other diseases of aging. The candidate is a physician-scientist with a strong commitment to a career in academic medicine focused on identifying strategies to protect against neurodegenerative conditions of aging, such as Alzheimer's disease and related dementias. The candidate has a PhD in neuroscience and an MD with clinical training in neurology and subspecialty training in dementias. The research proposal and career development plan build upon her training in neuroscience, aging, and neurodegenerative conditions to provide expertise in transgenic mouse models of Alzheimer's disease, behavioral analysis, histology, cell culture and viral vectors. The mentoring and research experience described in the proposal would provide resources, salary.
Although Alzheimer's disease (AD) devastates the minds of millions of people, there are no truly effective treatments. This proposal is aimed at developing strategies to protect the brain against AD by investigating newfound protective actions of collagen VI, a protein whose effects in the brain are virtually unknown. The mechanisms of this protection may be direct targets for developing effective AD treatments.
|Yokoyama, Jennifer S; Marx, Gabe; Brown, Jesse A et al. (2017) Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav 11:391-400|
|Dubal, Dena B; Zhu, Lei; Sanchez, Pascal E et al. (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci 35:2358-71|
|Orr, Anna G; Hsiao, Edward C; Wang, Max M et al. (2015) Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 18:423-34|
|Prather, A A; Epel, E S; Arenander, J et al. (2015) Longevity factor klotho and chronic psychological stress. Transl Psychiatry 5:e585|
|Dubal, Dena B; Yokoyama, Jennifer S; Zhu, Lei et al. (2014) Life extension factor klotho enhances cognition. Cell Rep 7:1065-76|