The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Abstract

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-β protein (Aβ), 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 Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ 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 Aβ 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 Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-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.

Microtubule shuttles on kinesin-coated glass micro-wire tracks

“…Kinesin uses adenosine triphosphate (ATP) as a fuel and its 8 nm step size corresponds to the size of the tubulin pitch forming the microtubule (Vale and Milligan, 2000;Hwang and Lang 2009). Due to their physiological importance, pharmaceutical targeting of microtubules and kinesin is under intensive study for diseases such as Alzheimer's disease and cancer (Zhou and Giannakakou, 2005;Craddock et al, 2012;Rath and Kozielski, 2012). Moreover, by virtue of in-vitro formation of microtubules (Weisenberg, 1972) and successful reconstruction of the kinesin/microtubule-based motility , this bio-motile system has been utilized as a model system for the study of pattern formation driven by motor proteins (Nedelec, 1997;Schaller et al, 2010;Sumino et al, 2012).…”

The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions

“…The mechanism of formation of Aβ fibrils has been modelled by several groups:

Kinetics of Aβ aggregation has been described using mathematical models 12, 13, 14, 39, 54, 55.

Activated microglia increases the production of Aβ through the secretion of Interleukin‐1 (IL‐1) whilst quiescent microglia helps to maintain Aβ production within a healthy range. Neuroinflammation associated with AD has been quantitatively investigated 41.

The transcription factor p53, when present in high levels, increases the activity of the protein kinase GSK3β leading to enhanced production of Aβ 16.Sequestration of zinc (Zn) by Aβ deposits triggers Aβ aggregation, which promotes plaque formation 15.Experimentally introduced anti‐Aβ antibodies in the brain have shown to reduce Aβ plaque levels. Models have been formulated to study the effect of immunisation against Aβ 34, 56.…”

“…Sequestration of zinc (Zn) by Aβ deposits triggers Aβ aggregation, which promotes plaque formation 15.…”

“…Another prominent feature in AD is Tauopathy, which is the accumulation of hyperphosphorylated Tau proteins; excessive Tau phosphorylation affects microtubule‐mediated transport within neurons, resulting in aggregation of Tau as pathological neurofibrillary tangles in the somatodendritic compartment. The regulation of Tau phosphorylation and the conditions that lead to Tau protein aggregation have been mechanistically investigated by various groups 15, 16, 17, 18…”

Zinc proteome interaction network as a model to identify nutrient-affected pathways in human pathologies

“…Due to its widespread functions throughout the body, zinc unbalance in specific tissues is likely to contribute to several diseases (Devirgiliis et al 2007). Zinc dyshomeostasis was associated with Alzheimer's disease and altered deposition of extracellular amyloid-b plaques (Craddock et al 2012). Decreased zinc content was also described in post-mortem pancreata of diabetic individuals over 75 years ago (Scott and Fisher 1938), and the role of this metal ion in insulin secretion and glucose homeostasis was confirmed since then by several reports (Chimienti 2013;Sladek et al 2007).…”