Alzheimer's disease (AD) is the most common type of dementia and it is the major cause of dementia affecting the elderly, accounting for 60-80% of all dementia cases. Although the mechanisms of AD are not well understood it is known that AD is a proteopathy leading to intracellular accumulation of tau protein and extracellular amyloid 2 (Ab) aggregates (senile plaques). When synaptically released Ab oligomerizes, and eventually aggregates, it leads to neuronal damage and an inflammatory response in glial cells through either direct toxicity and/or production of reactive oxygen species. It is not very well understood what triggers Ab oligomerization and aggregation in AD. One of the theories is the """"""""metal hypothesis of AD"""""""" which posits that extracellular metal ions, especially synaptically excreted Zn2+, instigate the Ab oligomerization and aggregation leading to the formation of senile plaques. Despite much progress supporting the metal hypothesis of AD, this idea remains a debated issue, partly because there is no adequate information on the binding and aggregation events at the timescale of synaptically released Zn2+. Clearly, a better understanding of the temporal patterns of Zn2+ signals is required together with a thorough insight into how these signals might trigger pathological oligomerization of Ab. This becomes especially important if there is a specific Zn2+ concentration window or a specific temporal pattern of the Zn2+ signals that would allow the formation of soluble oligomers, which are thought to be the most toxic, but not their aggregation into plaques which possibly protect against toxicity. In spite of enormous efforts in research, presently there is no treatment available for AD. It has been shown that chelation of Zn2+ can ameliorate plaque formation in animal models of AD, and accordingly, Zn2+ chelators have been suggested as a potential treatment for AD by preventing Ab oligomerization. Modulators of Zn2+ buffering pathways also hold promise for drug development in AD. Understanding the biophysical processes underlying the oligomerization of Ab as well as insights into the temporal patterns of Zn2+ signals that drive oligomerization are essential for developing such drugs. We have devised an ultra-fast in vitro kinetic measurement technique of Ca2+- binding to calcium binding proteins following flash photolysis of caged Ca2+ and created a compartmental kinetic model that resolved for the first time the cooperative nature of Ca2+ binding. This technique will be adapted to measure the fast Zn2+ binding kinetics by uncaging Zn2+ in the presence of Ab while optically monitoring Zn2+ binding dynamics. The same will be done to measure the Zn2+ binding dynamics of the Zn2+-binding protein metallothionein-3 (MT-3) which is enriched at Zn2+ releasing synapses. Our approach allows the unprecedented possibility to simulate extracellular Zn2+ signals as they are thought to occur at synapses. Studying the dynamics of Zn2+ binding to Ab and to other proteins under conditions resembling those at synapses will provide a first direct distinction between the physiological and pathological roles of Zn2+ in Ab oligomerization, resulting in the potential development of new and highly effective drugs for AD.

Public Health Relevance

It has been shown that reducing zinc (Zn2+) release in the brain can ameliorate plaque formation in animal models of Alzheimer's disease (AD). Accordingly, modulators of extracellular Zn2+ levels have been suggested as potentially an effective treatment for AD by preventing the formation of senile plaques. This project will determine when naturally occurring Zn2+ signals drive Ab oligomerizatoin which underlies formation of senile plaques and many other the symptoms of AD. With the acquired insight it should be possible to design drugs that specifically target pathological Zn2+ signals that may cause AD while minimally disturbing the Zn2+ signals necessary for normal brain functioning.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Biophysics of Neural Systems Study Section (BPNS)
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Refolo, Lorenzo
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Faas, Guido C; Mody, Istvan (2014) Measuring the steady-state properties of Ca²? indicators with a set of calibrated [Ca²?] solutions. Cold Spring Harb Protoc 2014:758-62
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Faas, Guido C; Mody, Istvan (2014) Measuring the Ca²?-binding kinetics of proteins. Cold Spring Harb Protoc 2014:691-3
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