IEEE 7th BIBE Invited Keynote Lecture: Metallobiochemistry of Alzheimer's Disease and Its Theranostic Agent Development

Alzheimer's disease (AD) has become a leading public health issue due to our nation's burgeoning aging population. These issues are further complicated by the fact that neither preventive measure and effective treatment nor definitive
in

vivo
diagnostic tool for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data argue that Abeta amyloidosis, which originates from the Abeta amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon this age-dependent protein disorder in brain are not well recognized. Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principle component of Abeta amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial and disordered protein-Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in post-mortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II), and to a lesser extent, Fe(III), are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS)-hydrogen peroxide (H
₂
O
₂
) and hydroxyl radical (OH
^.
). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H
₂
O
₂
mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5'untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE) which is consistent with biochemical evidence that APP is redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease. In addition, the AD diagnosis currently relies on behavior-based tests-e.g., Mini-Mental State Examination (MMSE). However, it is not specific for AD as many factors may lead to memory impairment and cognitive failure. The only definitive diagnosis for AD is the post-mortem examination of brain tissue for cerebral Abeta amyloidosis, the neuropathological hallmark of AD (2,3). Thus, development of in vivo amyloid imaging agents can not only provide definitive AD diagnostic tools but also speed up the preclinical and clinical assessment of novel AD therapeutic agents targeting Abeta amyloid. In summary, study of AD metallobiochemistry cements a solid foundation for discovering novel theranostic agents of AD.