Inhibitors or molecules for the treatment of AD

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The aim of most drugs developed for the treatment of Alzheimer's disease (AD) is to reduce the accumulation of amyloid- peptide (A) in the brain, a hallmark of the disease. Now, in a collaborative study, Merchier and De Strooper's research groups have identified the orphan G-protein-coupled receptor GPR3 in a functional genomics screen and validated it as a potential new therapeutic target.

The authors screened a library of adenoviruses encoding nearly 2,000 potential drug targets for modulators of A production. In addition to confirming previously identified targets, such as amyloid precursor protein (APP), the serotonin receptor HTR2C and the prostaglandin receptor PTGER2, they found novel regulators of A secretion in HEK293 cells expressing APP. The authors chose to focus their efforts on GPR3 as its gene has been mapped to a chromosomal locus that is associated with increased risk for AD and is highly expressed in regions of the brain that are affected as the disease progresses.

RNA interference-mediated knock down of GPR3 reduced A secretion by 50% without affecting the cells' general secretion and transport mechanisms. A results from the sequential cleavage of APP by - and -secretases, but immunoprecipitation and mass spectrometry analyses revealed that both the levels and the activity of -secretase were unaffected by GPR3 expression. Instead, GPR3 is likely to exert its effects by promoting the -secretase cleavage of APP, as co-expression of the -secretase substrate APP-C99 and GPR3 in hippocampal neurons substantially increased A release. Consistent with this finding, GPR3 expression increased the formation and cell surface localization of the mature -secretase complex, and treatment with a selective -secretase inhibitor abolished the effects of GPR3 on A secretion.

The authors also showed that GPR3 expression in mouse hippocampus increased A production, whereas in hippocampal neurons of Gpr3^-/- mice both mature -secretase complex formation and A release were markedly decreased. Moreover, when GPR3 was genetically ablated in a mouse model of AD, the levels of A were dramatically reduced.

The ability of GPR3 to modulate the effect of -secretase on APP but not on other substrates — Notch processing was not affected — reveals a new level of -secretase processing specificity. Together, these data highlight the key role of GPR3 in A production and the potential of GPR3 inhibitors or molecules that selectively target -secretase's activity towards APP for the treatment of AD. ...Nature Reviews Neuroscience 10, 246-247 (April 2009)

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