Kinetics of Abeta peptide deposition: Toward in vivo imaging of Alzheimer's disease amyloid.

摘要

Alzheimer's Disease (AD) is currently a major cause of morbidity and mortality among the elderly, affecting up to twenty million people worldwide and ranking as the third leading cause of death in the elderly population (in the developed world) behind cardiovascular disease and cancer. Unless effective preventive and therapeutic tools are developed, the number of affected individuals will double with increases in the demographic age of the world population in the next quarter century.; The defining pathological feature of AD is the development of extracellular amyloid plaques in the brain composed primarily of the Aβ peptide. Presently, there are no definitive, specific, objective (symptom-independent) tools for detecting Aβ amyloid in the brains of living patients. Diagnosis of AD is confirmed only post-mortem at autopsy. The ability to detect and quantify Aβ amyloid in vivo would provide researchers and clinicians with the tools necessary for efficient diagnosis and evaluation of the progress of AD, the relationship of Aβ amyloid burden to disease symptoms, and the effect of candidate therapeutics aimed at inhibiting Aβ amyloid accumulation.; This thesis describes work directed at developing the tools necessary for monitoring Aβ amyloid accumulation in the progress of AD in living animals by noninvasive imaging. Imaging Aβ amyloid noninvasively was first approached with the objective to further develop what is known about the fundamental characteristics of Aβ amyloid growth, then use what was learned about this process to develop Aβ peptide derivative radiotracers for use in in vivo imaging.; Experiments investigating the Aβ amyloid accumulation processes advanced the understanding of the mechanisms by which normally nonpathogenic Aβ peptides interact and develop into toxic Aβ amyloid. This work also provides insight into AD phenotypes associated with genetic mutation (Aβ-E22Q “Dutch” mutant), predisposition (apoE4 isoform), and normal age-related pathology (oxidative stress).; By leveraging what was learned about the amyloid growth process, the first known demonstration of specifically detecting and imaging Aβ amyloid in vivo was accomplished. Details of the design, synthesis, and characterization of Aβ peptide radiotracers for use as in vivo Aβ amyloid imaging agents are presented herein and correspond to real progress toward definitive pre-mortem diagnosis of AD.