New molecular target identified for the prevention of Alzheimer's disease
SummaryThe market for Alzheimer's therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Alzheimer's disease market in the seven major markets is worth $4.7 billion and will increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010. The major unmet need in this market is for disease modification and disease prevention. Recent findings by British researchers showing that targeting the neuronal adaptor protein X11beta can r
DailyUpdates 30th September, 2004: The pharmaceutical market for the treatment of neurodegenerative disorders will grow by an unprecedented amount over the next ten years. The aging of the baby-boom generation, combined with new and improved treatments for neurodegenerative disorders such as Alzheimer's and Parkinson's disease will lead to an expansion of the already multi-billion neurodegenerative market. The market for Alzheimer's therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Alzheimer's disease market in the seven major markets is worth $4.7 billion and will increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010.
The current management of Alzheimer's disease currently focuses on symptomatic treatment. Neuroleptics for are employed for aggressive behavior and antidepressants are also frequently used. Acetylcholinesterase inhibitors offer a corner stone of Alzheimer's therapy, with leading agents such as Pfizer/Eisai's Aricept (donepezil) used to slow cognitive and behavioral decline. Currently the only approved neuroprotective therapy is memantine.
The major unmet need in this market is for disease modification and disease prevention. Currently marketed products are perceived to only provide partial and temporary relief from Alzheimer's symptoms. In the short to medium term opinion leaders are looking to Axonyx's phenserine and Neurochem's Alzhemed in anticipation of successful modification of disease progression (for a list of further reading on the market and therapeutic development within the Alzheimer's disease arena click here).
Research in Alzheimer's disease still aims at elucidating the basic pathomechanisms in order to identify novel disease modifying agents. Defective processing of the Alzheimer’s disease amyloid precursor protein (APP) is a key etiological component of the disease. This type-1 membrane protein is proteolytically processed to produce beta amyloid 40 and 42 with accumulation of the latter in the brains of patients with Alzheimer’s being particularly neurotoxic and representing a fundamental early event in disease progression. Cleavage of APP involves sequential proteolysis by beta- and gamma-secretases (BACE1 & presenilin respectively).
X11beta (also known as munc-18 interacting protein-2; mint-2) and X11alpha are both neuronal adaptor proteins expressed in the brain and which are involved in the formation of multi-protein complexes in the brain. These molecules contain a number of protein-protein interaction domains through which it binds specific ligands including amino terminal sequences that bind APP. Both X11 subtypes inhibit production of beta amyloid in transfected non-neuronal cells. X11alpha has also been shown to inhibit production and deposition of beta amyloid in the brains of transgenic mice.
Researchers at The Institute of Psychiatry, Kings College London have now created X11beta transgenic mice and crossed these with transgenic APPswe Tg2576 mice which, like Alzheimer's disease patients, have increased levels of beta amyloid, develop amyloid plaques and are one of the best characterized models of Alzheimer’s disease amyloidosis.
In their upcoming Journal of biological Chemistry paper, Lee et al report the effect of X11 beta over-expression on 10 month old APPswe Tg2576 mice which are characterized by a 100-fold increase in beta amyloid 40 and 42 levels, insoluble beta amyloid, and the presence of plaques. Although X11 beta over-expression had only a small effect on the level of soluble beta amyloid 42, it reduced insoluble levels by 45%. The effect was preferential towards the heavier form of beta amyloid since beta amyloid 40 levels were reduced by only 18%. X11 beta over-expression also induced a 51% reduction in the number of beta amyloid deposits in the brain and decreased the diameter of those remaining plaques by around 30%.
This exciting data opens up new avenues for the development of therapeutic agents that may modulate the expression or activity of X11 beta and may which in turn target the pathophysiological mechanisms of Alzheimer's disease. Such an approach holds real promise for the development of much needed disease modifying therapies.
Source: J Biol Chem. 2004 Sep 3 [Epub ahead of print]
This article is highlighted in the September 30th edition of DailyUpdates-CNS Diseases, LeadDiscovery's unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today's bulletin click here
(Editorial note: In depth reports on cardiovascular disorders can be found at LeadDiscovery's report center or click here for suggested reading on Alzheimer's disease)