I was thinking about this subject for a while, not the least because my mother suffers from Alzheimer’s. In this disease, aggregation of amyloid-β peptides is widely thought to play a key pathological role. It is clear that prevention of the amyloid-β plaque formation would prevent memory loss. This strategy represents a potential for therapeutic intervention through a disease-modifying mechanism. A question arises regarding the biochemical path to the formation of amyloid-β peptides. Several enzymes contribute to the build-up of plaques. Of these enzymes, gamma- and beta-secretases have received a significant amount of attention from the research community. The enthusiasm in the early days of this research was grounded in the idea that inhibitors of gamma- and beta-secretases might block the production of amyloid-β plaques. Recently, however, gamma-secretase research has suffered a serious blow because a phase III clinical trial testing the inhibitor semagacestat failed (http://www.sciencedirect.com/science/article/pii/S009286741401304X). This led to closure of promising investigations aimed at inhibiting gamma-secretase and leaves behind beta-amino secretase as the best currently available target to prevent the formation of amyloid-β peptides. A seminal study by Stefansson et al. recently identified a missense mutation (A673T) in the amyloid-β precursor protein (APP) gene that protects against Alzheimer’s disease (http://www.nature.com/nature/journal/v488/n7409/full/nature11283.html). The mutation was identified by the analysis of the genome sequence data of 1795 Icelanders. I am truly amazed by the enabling features offered by the genetic makeup of this unique population. Interestingly, the A673T missense mutation reduces cleavage of APP by the beta-secretase BACE1. This finding supports the hypothesis that abnormal processing of APP causes Alzheimer’s disease. Significantly, the Stefansson paper further validates BACE1 as the legitimate target in search of treatment against Alzheimer’s disease.
Apart from achieving blood-brain barrier penetration by BACE1 inhibitors, minimizing the inhibition of cathepsin D (CatD) is the obstacle that faces this research. CatD is an aspartyl protease with high sequence homology to BACE1 at the active site. It has been shown that the inhibition of CatD gives rise to toxic side effects. Once these two hurdles have been overcome, there will likely be a cure for the Alzheimer’s disease. Below, by the way, you can see a picture of the first report of BACE1 co-crystallized with a peptide inhibitor some 15 years ago (pdb id 1FKN).
nearly-identical active site may not be identical from a plasticity point of view – a substituent in the right place in the ligand can poke a hole – opening a new binding pocket – in the binding site wall of one target. This cannot be predicted a priori, only testing collections of small molecules and doing a co-crystal can reveal this sort of selective induced fit binding mode.
A difficulty with Alzheimer (and Parkinsons) is that by the time it manifests itself the pathology has been going on for maybe 10 years already, so you are trying to treat a brain that already underwent a major neuronal loss, the remaining neurons being quite unhealthy, and with a chronic inflammatory component, and there are age-related changes in vasculature that really make it worse.
(I remember reading about long-term cognitive studies in nuns followed post-mortem pathology examinations of their brains. many of them remained perfectly sharp even into their nineties, despite having lots of amyloid plaques. But they did not have much arteriosclerosis. The conclusion was that the plaque formation could be compensated for by the brain, to a some degree, as long as there is no underlying vasculature problem like microscopic strokes)
This is interesting, I agree that the progression of this ailment continues to be a mystery… In addition, Susan Lindquist at MIT has evidence that speaks to the importance of maintaining plaque homeostasis. In other words, they are also having some protective function. This is complex.
the convent nuns are such great study subjects since they live in almost controlled environment, have a thorough medical history records, abstain from alcohol and fast food, etc.
Very cool point, I am not sure this has ever been leveraged…