Another Piece of the Alzheimer's Puzzle is Revealed

Previously, here and here, I discussed the connection of apoE4 and NMDA glutamate receptors with Alzheimer's disease and neuronal cell death. Here is some followup research from Georgetown University on the relationship of apoE4 and the NMDA glutamate receptors, with Alzheimer's Disease. This study establishes the connection in more detail.

In a study published in the Journal of Biological Chemistry, the research team specifically found that receptors on the outside of brain nerve cells that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein.

While the researchers don't know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories.

....in this study, they confirmed through a series of experiments that the receptors for APOE and NMDA interacted, and that the protein that linked the two was PSD95, often found in neural synaptic junctions. Together, they form a multiprotein complex that could presumably be activated by either APOE, NMDA or glutamate.


Looking back at previous research:

....Based on recent research, Rebeck and others suspect that, in the brain, APOE also acts as a transporter, picking up lipids and perhaps other material that result from normal brain tissue wear and tear, or from trauma, and moving it to where it can be used or can be cleared away from the brain. Work in Rebeck's lab found that APOE receptor 2 ( ApoEr2 ), one of the eight different APOE receptor types, is crucial to both the development and operation of a normal brain.

Glutamate increases the strength of a synaptic response following stimulation. The NMDA glutamate receptor binds on to the drug NMDA, and also on to glutamate, an excitatory neurotransmitter that also stimulates nerve cell activity. Researchers know that the NMDA receptor is needed to produce the long-lasting synaptic response that is necessary in order to establish, or "lay down," memory, Rebeck says. " The molecular basis of memory depends on NMDA receptor. "

In work leading up to this study, Rebeck and the research team found that adding APOE to neurons in laboratory culture blocked NMDA receptors.

....Rebeck suspects that the APOE4 variant -- the one linked to Alzheimer's disease -- is less efficient at removing lipid debris in the brain than is APOE2 or APOE3, and because of this, brain cells secrete more of the faulty protein to do the job. If too much APOE ends up binding to the APOE/NMDA receptor, one of two things could possibly happen, Rebeck says. In one scenario, the receptor becomes over-stimulated due to the accumulating presence of APOE, which could trigger a process called excitotoxicity that results in death of the neruons. Or, in the presence of damage and secreted APOE, the receptor "turns down" its activity -- thus, hampering memory formation -- until the brain is repaired. " Having damage around tells the brain not to think too much for awhile, " Rebeck says. But if APOE4 cannot clear up accumulating damage, the ability to make new memories, and use old ones, may be increasingly lost. More at the source.

This is how research progresses, step by step--each step based upon earlier findings by the same researchers and/or other researchers around the world pursuing the same sets of leads. With each new piece of the mechanism identified, another potential target for protecting neurons from degenerative processes is uncovered.