In vitro vs. In vivo Alzheimer's Research and the Brain Environment

One of the major problems with research related to Alzheimers Disease pathogenesis is being able to appropriately mimic the pathogenic brain environment in vitro. Alzheimer Disease is related to the activation of microglial cells via its interaction with fibrillar Amyloid Beta plaques. However, the microglial cells have an array of phenotypically distinct activated states. In one case the microglial cells are activated in the classical M1 state, which is a state that corresponds to high expression of pro-inflammatory cytokines, another is called the M2 activated state which has a more immunoregulatory profile. The phenotypes get even more complex when now the M2 state can be subdivided into categories M2a, M2b, and M2c, all with there own distinct cytokine releasing profile. These different activation states are all regulated by the glial cells surrounding environments. This hasn't been a problem in vitro, because researchers can make there own environments and measure what comes of the activated cells, however in vivo they don't have this luxury because all these environments and activation states are working together, which is why it has been so difficult to successfully define the pathogenic mechanism of Alzheimer's.

A good example of this was stated in an article recently published in the Journal of Neuroscience, it was saying that Toll like receptors (TLRs) have a definitive role in the activation of glial cells response to Amyloid Beta plaques in vitro, but in vivo mice models with AD the situation is much less clear. Some transgenic mice with inactivated TLR's saw an increase plaque accumulation while others had extremely delayed plaque deposition. This obviously shows that however in vitro research can show such concrete findings, things get so much more complicated in the in vivo environment. I wasn't really aware of this, I always thought that we were at such an advanced stage of research that these types of problems were long gone. So to me this is a little disheartening, it says that we are a long ways away from finding a distinct cause, let alone a cure for this horrible debilitating disease.

The Journal of Neuroscience Article explaining this: ishttp://www.jneurosci.org/cgi/content/abstract/30/46/15369