Treatment of neurodegenerative diseases

Abstract

Use of selenate or a pharmaceutically acceptable salt thereof in methods and compositions for enhancing the activity of the protein phosphatase PP2A is provided. Methods of reducing phosphorylation of tau protein, inhibiting activity of GSK3 and treating or preventing neurodegenerative diseases are also described.

Description

FIELD OF THE INVENTION[0001]This invention relates to the use of selenate or a pharmaceutically acceptable salt thereof in methods and compositions for enhancing the activity of PP2A. The present invention also relates to the use of selenate or a pharmaceutically acceptable salt thereof in methods of inhibiting or reducing phosphorylation of tau protein, in methods of inhibiting the activity of GSK3β and particularly in methods of treating or preventing neurodegenerative diseases. In some embodiments, the invention relates to the use of selenate or a pharmaceutically acceptable salt thereof in combination with other therapies for use in methods of treating or preventing neurodegenerative diseases.BACKGROUND OF THE INVENTION[0002]Neurodegenerative disease is a general term for a number of disorders that act by compromising the brain's capacity to control itself or the body by damaging neurons that facilitate normal brain function. Neurodegenerative diseases are primarily diseases of ...

AI Technical Summary

Benefits of technology

[0021]The present invention is predicated in part on the discovery that the activity of the protein phosphatase PP2A can be enhanced by exposure to selenate or a pharmaceutically acceptable salt thereof. The enhancement of the activity of PP2A can reduce or inhibit phosphorylation of tau protein, especially hyperphosphorylation, with a two pronged approach: i) dephosphorylation and inactivation of Akt, thereby reducing phosphorylation of GSK3β and consequently reducing phosphorylation of tau protein, and ii) direct dephosphorylation of tau protein. A reduction in the phosphorylation, especially hyperphosphorylation of tau protein reduces or prevents the accumulation or deposition of abnormal tau protein in neurons and glial cells and therefore is useful in the treatment or prevention of neurodegenerative disorders.

[0023]In another aspect of the invention there is provided a method of inhibiting or reducing phosphorylation of a tau protein in a neuron, glial cell or Lewy body, comprising exposing the neuron or glial cell to an effective amount of selenate or a pharmaceutically acceptable salt thereof. In some embodiments, the tau protein is a microtubule-associated tau protein. In some embodiments, the tau protein is in a neurofibrillary tangle. In some embodiments, hyperphosphorylation of tau protein is inhibited or prevented.

[0034]The term “hyperphosphorylation” refers to the circumstance where all available phosphorylation sites on a biochemical entity such as a protein, are phosphorylated. No further phosphorylation of the biochemical entity can occur. The phrase “inhibiting or reducing hyperphosphorylation” includes preventing all sites on a biochemical entity from being phosphorylated and decreasing the number of biochemical entities that have all of their phosphorylation sites phosphorylated.

[0054]Combination therapies could include effective amounts of selenate or a pharmaceutically acceptable salt thereof together with an agent used for treating or preventing a neurodegenerative disease in an amount normally used in the absence of selenate. For example, tacrine hydrochloride may be administered as part of a combination with selenate or a pharmaceutically acceptable salt thereof to patients with a neurodegenerative disease such as AD in an amount of 40 mg / day to 160 mg / day or donepezil may be administered in an amount of 5-10 mg / day. Premarin may be administered at a dosage to achieve 1.25 mg / day of conjugated equine estrogens (CEEs) in patients with dementia. Alternatively the amount of agent used in the treatment of neurodegenerative disorders may be decreased upon co-administration with selenate or a pharmaceutically acceptable salt thereof. In some embodiments, the combination may display a synergistic effect.

Problems solved by technology

Moreover, since α-Syn is known to bind to microtubules (Wersinger and Sidhu, 2005) with a possible role in axonal transport (Sidhu et al., 2004), it is likely that the dissociation of this protein from microtubules further aggravates the instability of microtubules, disrupting the cytoskeletal network and cellular homeostasis.

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