AD brains have two types of lesions: beta-amyloid plaques outside neurons, and neurofibrillary tangles within them. The known AD genes implicate plaques, but AD symptoms correlate more closely with tangles, comprised of "tau" protein, normally adhered to microtubules. Excess beta-amyloid plaques induce tangles, disrupt microtubules, and cause memory loss, even with normal synaptic function. But how?
In the March 23 issue of the journal PLoS One, scientists from Harvard, Boston University, The University of Alberta, The University of Arizona and The Chopra Foundation ascribe AD memory loss to disruption of microtubules by zinc imbalance.
Previously, Harvard’s Dr. Rudolph Tanzi, senior author on the present study, showed with colleagues that plaques outside neurons sequester zinc, lowering levels inside neurons. Zinc stabilizes many protein complexes, including microtubules (MTs), polymers of tubulin. MTs regulate synapses, and play recently-revealed key roles in memory encoding in neurons.
In the present study, Craddock et al 1) identify specific zinc-tubulin binding sites promoting side-to-side tubulin interactions, critical to MT polymer structure, 2) show via kinetic analysis how extra-neuronal zinc sequestration reduces intra-neuronal zinc available to tubulin, destabilizing MTs and leading to tangles. And, 3) they present metallomic imaging mass spectrometry (MIMS) of AD model mice revealing abnormal zinc distribution in critical brain regions.
This view of AD suggests therapies based on stabilizing MTs by 1) normalizing intra-neuronal zinc levels by zinc ionophore drugs such as PBT2 (Prana Biotechnology), and 2) promoting MT self-assembly and stability by other drugs, as well as transcranial therapies, e.g. ultrasound at MT resonant frequencies in megahertz.
Tanzi, senior author and Harvard’s leading Alzheimer’s expert said: “It looks like beta-amyloid plaques themselves aren’t destructive directly, but lead to lower zinc levels within neurons. This in turn disrupts microtubules and tau, causing tangles and memory loss. Protecting microtubules and their association with tau may be the best treatment approach in Alzheimers disease.”
Citation: Craddock TJA, Tuszynski JA, Chopra D, Casey N, Goldstein LE, Hameroff SR, Tanzi RE (2012) The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease. PLoS ONE 7(3): e33552. doi:10.1371/journal.pone.0033552 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0033552
Disclosure: Rudolph Tanzi is a consultant and shareholder in Prana Biotechnology, which is developing a zinc ionophore (PBT2) for the treatment of Alzheimer's disease.
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