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Wed poster from Prana ICAD
ICAD Wednesdays Poster Session 16-Jul-11 03:26 pm

Wednesday, July 20, 2011 Poster Session Conference: 2011 International Conference on Alzheimer's Disease Date: Wednesday, July 20, 2011 12:30 PM - 3:00 PM Poster Session Program Code: P4

Metal chaperones: A holistic approach to the treatment of Alzheimer?s disease P4-407 Background: Despite a variety of drug targets for Alzheimer?s disease (AD) being proposed, efforts to identify disease modifying drugs have been disappointing. Indeed the clinical failure of several anti-Abeta therapeutic agents has lead to the suggestion that this approach is only likely to be effective in pre-symptomatic individuals i.e. it is too difficult to treat patients actually suffering from AD. A key reason for why therapeutic strategies directed to these targets has not translated into clinical success may be due to their innate reliance on conventional reductionist approaches to disease treatment where a more holistic approach is required. The number one risk factor for AD is age; one of the consequences of aging is a breakdown in metal homeostasis. Metal ions such as Cu and Zn play key roles in regulating synaptic function and perturbation of metal homeostasis causes synaptic dysfunction which is implicated as the primary cause of memory deficits in AD. Extracellular pooling of copper and zinc promotes the aggregation, toxicity and proteolytic resistance of Abeta while the sequestration of metals by Abeta further exacerbates metal dyshomeostasis.

Methods: Our goal is to assess whether PBT2 a novel metal chaperone can neutralize Abeta toxicity and restore synaptic function in AD. A wide variety of preclinical studies have been used to determine PBT2?s suitability as a disease modifying agent for AD and it is currently undergoing clinical evaluation in AD and Huntington's disease.

Results: Not only can PBT2 prevent Abeta/metal interactions which give rise to toxic oligomers but acting as a metal chaperone PBT2 induces neuroprotective signaling cascades. This signaling which includes inhibition of the phosphatase calcineurin leading to increased p-GSK3beta, with decreased levels of phospho-tau also protects against glutamate induced excitotoxicity. PBT2 increases dendritic spine density and levels of proteins associated with learning and memory such as NMDA receptor subunits 1A 2A, CamKII and BDNF, a property strictly dependent on its ability to deliver metals

Conclusions: These data suggest that PBT2 represents a more holistic approach to treating AD in that it can reverse Abeta pathology, inhibit the actions of other proteins implicated in the disease process and reverse synaptic dysfunction. Kevin Barnham, The Mental Health Reseach Isntitute Robert Cherny, Prana Biotechnology, and The Mental Health research Institute