Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease

Ralph H Johnson Va Medical Center, Charleston SC

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting about 10% of those aged 65 or over, but no treatment to delay or halt the progression of the disease is as yet available. Under the present situation where the proportion of the elderly population is progressively increasing, AD has become a significant problem for the elderly citizens including Veterans. Therefore, the study of this disease is relevant to the mission of the Veterans Administration. Recently, new evidences indicate cerebrovascular complications and impaired regional cerebral blood flow as the causative factors in AD along with its associated memory loss and behavioral changes. In turn, this evidence provides the rationale for early treatment of cerebrovascular dysfunction which is critical for delaying, slowing down or preventing the development of AD. Nitric oxide (NO) plays an essential role in the maintenance of vascular tone and hemodynamics. Currently, free NO donors, such as sodium nitroprusside and nitroglycerine, are being used in various clinical settings. However, these NO donors, releasing free NO, may not be an effective treatment for AD because the concomitant chronic inflammation and oxidative stress scavenge free NO from these donors to generate deleterious peroxynitrite. Here, we propose to evaluate the therapeutic potential of GSNO, a major transport form of NO in biological systems, for the treatment of AD. GSNO is able to induce several cell signal transduction pathways that are essential for biological action of NO via S-transnitrosylation without generation of free NO. In addition, GSNO is implicated in anti-inflammatory, anti-oxidant, and vaso-protective effects under various disease conditions. Therefore, GSNO is a promising candidate as a stand-alone therapy for cerebrovascular complications implicated in AD. In support, we have recently observed that GSNO treatment inhibited the inflammatory response and also reduced A¿ accumulation and improved impaired learning and memory performance in aged rats with chronic cerebral hypoperfusion, an animal model for vascular dysfunction associated with late-onset AD, and in transgenic mice over-expressing human A¿. On the basis of these data, the following specific aims are designed to improve therapeutic reliability of GSNO in the treatment of AD, to optimize pharmacological parameters, and to investigate mechanisms underlying the drug action(s). Specific Aim 1: To establish therapeutic efficacy and pharmacological optimal dose of GSNO therapy for cerebrovascular complications associated with Alzheimer's disease: Under this aim, we propose to optimize the efficacy of GSNO treatment against cerebrovascular complications associated with development and progression of AD pathology. Two animal models will be employed for these studies: transgenic mice producing high levels of A¿ for studies of early-onset AD and aged rats received bilateral common carotid artery occlusion (BCCAO), a clinically relevant model for human mild cognitive impairment and associated late-onset AD. Specific Aim 2: To investigate the mechanism(s) underlying GSNO therapy: Implication of anti-inflammatory and vaso-protective activities of GSNO: Under this aim, we propose to investigate the mechanism(s) underlying GSNO mediated anti-inflammatory and vaso-protective signaling cascades in brain micro-vessel endothelial cells. Focus of this aim will be to study the S-nitrosylation of cell signaling mediators regulating gene expression for inflammatory mediators and A¿ clearance across the blood brain barrier (BBB). The results from studies described here should provide a better understanding of pharmacological, biochemical and cell biological events underlying vascular pathology of AD, and the possible utility of GSNO as therapeutics for the management of AD.