As explained in the previous post, Aβ catabolic pathway may offer an effective way to prevent as well as treat Alzheimer's disease (AD). The enzymes involved in Aβ degradation and clearance are- Neprilysin (NEP), Insulin Degrading Enzyme (IDE), various matrix metalloproteinases (MMPs) that degrade Aβ and low-density lipoprotein receptor-related protein 1 (LRP-1) located on Blood-Brain Barrier (BBB), which causes efflux of Aβ from brain to blood.

There is an ample evidence that all these enzymes are down-regulated in AD patients as compared to healthy individuals. In this context, up-regulating one or more of these enzymes by pharmacological or molecular biological means may help in preventing and treating AD. The recent reports support this hypothesis- increased levels/activities of NEP in the brain or in the blood was shown to significantly decrease Aβ levels in the transgenic mice [1]. There are multiple reports regarding similar role of IDE and MMPs in degrading brain Abeta. Similarly, LRP-1 upregulation has been shown to increase Aβ efflux from the brain [2].

In summary, up-regulation of these Aβ-catabolic targets offers a novel, effective way to tackle AD. This approach is gaining increasing attention and researchers are interested in finding pharmacological activators of these enzymes (NEP, IDE etc.). In this context, it is interesting to note that a pre-approved drug for epilepsy, epilim (sodium valproate), has been shown to significantly elevate NEP levels [3].

The AD field looks forward to dditional success stories like this in near future, which may pave a way towards an effective therapy against AD. Currently there are around 5 million AD patients in US itself and the cost associated with them is staggering $142 billion. The number of AD patients is estimated to increase exponentially in coming years and there is an obvious urgency for effective drug(s) that will prevent, treat or at least slow down AD progression.

The paradigm shift in drug discovery towards Aβ-catabolic targets (NEP, IDE etc.) as opposed to Aβ-anabolic targets (BACE1 and γ-secretases) may help us in achieving this goal.

References:

[1] http://www.alzforum.org/new/detail.asp?id=1979

[2] Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, Van Nostrand W, Miano JM, Zlokovic BV. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):823-8.

[3] Belyaev ND, Nalivaeva NN, Makova NZ, Turner AJ. Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease. EMBO Rep. 2009 Jan;10(1):94-100.