Dr. Ron’s Research Review – December 11, 2013

© 2013

This week’s research review focuses on the zinc and Alzheimer's disease.

Zinc Deficiency

Brewer proposes that zinc deficiency along with inorganic copper in drinking water may cause Alzheimer's disease. They conducted a 6-month small double blind trial of a new zinc formulation on AD patients. In patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls, and significantly lowered blood free copper levels. (Brewer and Kaur 2013)

Zinc Excess

During traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. (Szewczyk 2013)

Zinc Dyshomeostasis

The zinc dyshomeostasis hypothesis of Alzheimer's disease proposes that sequestration of zinc by Abeta-amyloid deposits (Abeta oligomers and plaques) not only drives Abeta 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. The proposed connection 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. (Craddock, Tuszynski et al. 2012)

Dr. Ron


Articles

Zinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer's Disease

         (Brewer and Kaur 2013) Download

We are in the midst of an epidemic of Alzheimer's disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls. We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both.

The zinc dyshomeostasis hypothesis of Alzheimer's disease

(Craddock, Tuszynski et al. 2012) Download

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 (Abeta), 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 Abeta accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Abeta and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Abeta-amyloid deposits (Abeta oligomers and plaques) not only drives Abeta 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 Abeta 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 Abeta 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.

Zinc homeostasis and neurodegenerative disorders

         (Szewczyk 2013) Download

Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging.

References

Brewer, G. J. and S. Kaur (2013). "Zinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer's Disease." Int J Alzheimers Dis 2013: 586365. [PMID: 24224111]

Craddock, T. J., J. A. Tuszynski, et al. (2012). "The zinc dyshomeostasis hypothesis of Alzheimer's disease." PLoS One 7(3): e33552. [PMID: 22457776]

Szewczyk, B. (2013). "Zinc homeostasis and neurodegenerative disorders." Front Aging Neurosci 5: 33. [PMID: 23882214]