Research Topic: 3. Alzheimer's Disease Drug Discovery. Recent clinical reports indicate that the onset of Alzheimer's disease (AD) is earlier with prior mild neurologic insults or with increasing prior anesthetic exposure. The specific characteristics of anesthesia history that predispose to this earlier onset of AD are unknown but such observations raise the concern that something about anesthesia may constitute a mild neurologic insult. NMDA antagonists such as nitrous oxide (N20) and MK801 have been demonstrated to have a bimodal dose-related protective and then neurotoxic effect in normal rodents, with congruent regional activation by N20 reported in humans. There is ample data indicating an important role for neuroexcitation with associated oxidative injury in the pathogenesis of AD. It thus becomes reasonable to suggest an interaction between the genesis of AD and prior N20 exposure. Clinically N20 is an extremely common anesthetic with virtually ubiquitousexposure by almost everyone at some point in life. This makes its use a reasonable and potentially immensely important area to explore in the pathogenesis of AD. We hypothesize that N20 exposure has a bimodal dose-related effect to either attenuate or exacerbate subsequently developed AD. We will test the specific hypotheses that: 1. High dose N20 exposure exacerbates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive five high-dose exposures to N20 during middle-aged, or elderly ages followed at age 10 months by cognitive assessment, analysis of brain isoprostanes as markers of peroxidation and soluble andinsoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration 2. Low dose repetitive N20 exposure attenuates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive low doses of N20 nightly from mid-life to elderly ages, followed at age 10 months by cognitive assessment, analysis of brain isoprostanes and soluble and insoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration. Anesthesia has been implicated in postoperative cognitive dysfunction (POCD) in the elderly and has been impugned in the early onset of AD. The proposed research will explore the potential contribution of a ubiquitous anesthetic with neuroexcitatory side effects in a relevant murine model of AD. This will contribute to a focussed evaluation of the potential causes of POCD the results of which will change the practice of anesthesia and thus significantly attenuate the incidence of POCD in the elderly and possibly impact on the epidemiology of AIzheimer's disease. Moreover, observation of a protective effect may result in discovery of an easily implemented preventative drug therapy for AD.
