Increasing sensitivity to environmental stress by humanizing NOS2 in mouse.

Challenge and potential impact of metabolic syndrome on dementia: As our population ages, chronic diseases of the brain continue to increase with estimates now of 5 million US citizens suffering from Parkinson's disease (PD) and Alzheimer's disease (AD). Worldwide prevalence estimates are staggering. The Delphi consensus study in 2005 estimated 1 new case of AD every 7 seconds with a higher rate of increase in developing countries ^1. The economic impact is equally staggering. In addition to health care costs, the informal costs associated with caregiving by family members was approximately $20,000 per patient in 2012. At the recent 24th Annual Conference of Alzheimer's Disease International in March 2009, a total worldwide societal cost was estimated to be $315 billion dollars (www.medicalnewstoday.com/articles/143551.php). Although the potential for developing useful therapies that delay onset of AD will alter the prevalence estimates, the economic, social and personal impact of these neurodegenerative diseases is a major public health issue and will remain a severe public health issue till at least 2050. Outside of the studies that have identified human mutations as a basis for disease onset and progression, the vast number of individuals with sporadic AD and PD have an unknown etiology. Unquestionably these are multifactorial diseases where environment plays critical roles.

Obesity is also on the rise. The National Health and Nutrition Survey for 1999-2000 showed that almost 65% of adults in the U.S. are overweight, i.e. their body mass index (BMI) is greater than 25 kg/m2; 31% of those are obese, with BMI>30. This surge in obesity has dramatically increased the prevalence of type-2 diabetes, which now affects even children. In both children and adults, the abdominal obesity in particular is linked to increased risk for development of metabolic syndrome. The connection of dyslipidemia, central obesity, insulin resistance and diabetes to late life dementia is also strong. Although some association studies have shown inconsistent risk outcomes, recently a large meta-analysis review of multiple published studies establishes that obesity and diabetes have significant and independent effects on increased risk of Alzheimer's disease. While the APOE4 allele effect remains the most significant risk factor for AD and other neurological disorders, this susceptibility gene together with environmental factors such as stress and over-nutrition increases the risk of dementia to unacceptably high levels. The combined effects of dyslipidemia, central obesity, insulin resistance and diabetes (collectively called metabolic syndrome) to AD in late life are consistent with a slow disease progression that begins many years before clinical signs and symptoms. The impact of stress and obesity over a long time period has been recently shown even on a cell biological level. The Sister Study sponsored by NIEHS suggests that environmental inputs such as perceived stress alter teleomere length in human subjects, resulting in mistakes in DNA during cell replication 8, 9. Environmental factors may be modified to reduce the risk of neurodegeneration, or in the least, to slow its onslaught.

The association studies of populations at risk have pointed to multifactorial pathways that are shared by neurodegenerative disease and metabolic disorders. At least two broad based pathophysiological systems are implicated in both; these are the innate immune response and tissue redox balance. The specific factors or mechanisms within these systems that mediate the effects of environment on chronic neurodegenerative disease are unknown.

In this proposal we will develop a mouse model of disease that combines environmental factors- stress and over-nutrition- with a genetic manipulation that "humanizes" the mouse innate immune response and redox balance

Selection of those genes to humanize is obviously a daunting task. We have chosen to use the dual concepts of innate immunity and redox balance to alter gene function in mouse models. The gene we have chosen to change is nitric oxide synthase 2 (NOS2) that codes for immunological (inducible) NOS. The scientific rationale behind the preparation of this mouse strain is based 1) on the role of iNOS in an innate immune response, 2) on species-specific differences in the NOS2 gene between humans and rodents and 3) on immunosuppression of NOS2 in chronic disease as compared to acute disease. Importantly nitric oxide also plays a key role as an anti-oxidant to preserve tissue re-dox balance. Thus, NOS2 is at an intersection point between innate immunity and redox balance, two of the shared features of metabolic syndrome and chronic neurodegeneration. Similarly, life conditions of mice can be "humanized" by exposing them to stress and Western-type diet, rich in fat and sugar. Recently, such a "humanized" model of metabolic syndrome was developed by the Zukowska lab 1 where stress accelerated and amplified diet–induced abdominal obesity, and speed up development of atherosclerosis/restenosis. We will use this stress-induced model of metabolic syndrome together with the "humanization" of NOS2 to create a novel murine model of AD, and to better recapitulate this unfortunately common and unforgiving chronic human disease.