Environmental exposure to lead (Pb) has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although Pb has long been known as a neurotoxic agent in children, a recent and growing body of both toxicological and epidemiological research indicates that cumulative environmental Pb exposure is toxic to adults as well, and may be a significant contributor to age-related neurologic dysfunction. The biological mechanism underlying this link is not known. It has been proposed based on a limited number of animal studies that the linkage is through epigenetic changes in the methylation state of DNA, although evidence for this mechanism in human disease has been lacking. This proposal considers another possibility, that the linkage is through a combination of Pb-driven neuropathologic change, and that cerebrovascular pathology is the major contributor to this form of neurologic dysfunction. The amount of cerebrovascular pathology is a significant co-morbidity in all forms of age-related dementia. Most individuals with AD have some degree of comorbid cerebrovascular pathology, although individuals with a history of obesity and T2DM have substantial amounts of this pathology. To investigate this problem, we created a line of knock-in mice that co-develops amyloid pathology and cerebrovascular abnormalities with increasing age. The most remarkable feature of this novel mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and also displays a profound cognitive impairment. We believe that we have created an innovative model of AD with significant cerebrovascular disease, an understudied variant with limited treatment options. The unique db/AD mouse does not overexpress disease related proteins or use artificial promoter systems, making it an ideal system for the study of how aberrant gene regulation in disease can influence brain pathology. This presents an unparalleled opportunity to study, and potentially dissociate the role of Pb exposure at different times in an animal's lifespa and gauge the ultimate impact on neuropathology. This proposal thus seeks to answer three key questions relating to Pb exposure and neurologic disease that occurs later in life. First, is early life Pb exposure more damaging than exposure as an adult? Second, can Pb cause late-life cognitive dysfunction by increasing cerebrovascular pathology, such as strokes, through increased hypertension, a well-known outcome of Pb exposure? Finally, how much does Pb exposure affect the development of AD-related pathology by affecting the expression of AD related genes? We believe that our mouse model is uniquely suited to answering these questions. A major innovative feature of this proposal is the use of a novel mouse model with unique features, exhibiting significant age associated AD-related amyloid deposition, cerebrovascular pathology, and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease, but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as comorbidity in the AD brain.
A strong connection exists between risk for vascular dementia, Alzheimer's disease, type 2 diabetes (T2D), and obesity, but the mechanisms are unknown. The connection may involve strokes, and other forms of cerebrovascular pathology. This project will investigate the role of environmental lead exposure as an underlying risk factor in this complex disease state.
|Platt, T L; Beckett, T L; Kohler, K et al. (2016) Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease. Neuroscience 315:162-74|
|Helman, Alex M; Murphy, M Paul (2016) Vascular cognitive impairment: Modeling a critical neurologic disease in vitro and in vivo. Biochim Biophys Acta 1862:975-82|