How Alzheimer’s starts

To picture how Alzheimer’s unfolds in brain cells, think of a neuron as a top-security government office. Then imagine a pair of foreign spies approaching a sleeper agent who works there. That agent is a crucial link: when she lets in the spies, she will start a chain of events that will bring down the government.

We know who the spies are; one of them, amyloid beta oligomer (Aßo), makes up the plaques that clog spaces between cells in brains afflicted with Alzheimer’s. We also have an inkling of the chain of events inside the cell. But until recently, no one knew the identity of the sleeper agent.

Now Stephen Strittmatter, professor of neurology and neurobiology with the Yale School of Medicine, has found the culprit: a receptor called mGluR5. Brain researchers are already familiar with mGluR5. It’s a normal and necessary resident of the neuron’s membrane, interacting with molecules outside the cell and signaling to others within.

But in Alzheimer’s, Aßo and a normally occurring prion (PrP^C) link up at the cell surface. Then the prion binds to mGluR5, which in turn touches off several changes inside the cell—including activating an enzyme that binds to a protein called tau, which is behind the notorious tangles Alzheimer’s causes in brain cells. (Strittmatter’s discovery appeared in the August 4 edition of Neuron.)

Strittmatter hopes that blocking mGluR5 may help Alzheimer’s sufferers; thanks to all the research done previously on the receptor, we already know how to target it with drugs. When he gave mice with early-stage Alzheimer’s a blocker drug called MTEP, the mice recovered memory abilities and increased the density of their synapses. Unfortunately, too much MTEP can itself damage memory. Moreover, the mice hadn’t yet progressed to the stage of devastating neuron loss.

So a better drug, says Strittmatter, might be one that blocks mGluR5 only in the specific shape it takes in the development of Alzheimer’s. He is searching for such a drug now. The right one could stop mGluR5 from consorting with the enemy.