Paper Citing NAMD - Abstract
Craddock, Travis J. A.; Tuszynski, Jack A.; Chopra, Deepak; Casey, Noel; Goldstein, Lee E.; Hameroff, Stuart R.; Tanzi, Rudolph E.
The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease
PLOS ONE, 7 Art. No. e33552, MAR 23 2012
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-beta protein (A beta), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive A beta accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking A beta and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by A beta-amyloid deposits (A beta oligomers and plaques) not only drives A beta aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal A beta deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal A beta amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on beta-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.
