Circling In on Alzheimer's and Obesity

Could there be any two hotter topics in science these days than Alzheimer’s disease and obesity? Using the Google trend-o-meter – the ubiquitous search – turns up 18 million references for Alzheimer’s and a whopping 36 million for obesity. Comparable figures on Yahoo are 33 million and 51 million, respectively. While that pales next to cancer’s hundreds of millions, it does stagger the mind that with so much information bouncing around, so little knowledge seems to be crossing the goal line.

Perhaps we are all suffering from early stages of cognitive decline. I jest. Or more seriously, as UCSF neuroscientist Lennart Mucke, MD, reported at the recent “From Molecules to Medicine” mini-symposium at UCSF Mission Bay, some of us truly are experiencing nonconvulsive, hard-to-detect seizures in our learning and memory centers that could lead to Alzheimer's disease.

Indeed, as Mucke, director of the UCSF-affiliated Gladstone Institute of Neurological Disease, explained, there seems to be much more going on with Alzheimer’s than loss of neurons or a disruption of synapses would suggest. Circuits and networks also have to be involved.

For anyone who has spent time with an Alzheimer’s patient, Mucke’s notion, as reported in Neuron, seems right on target. How else to explain how the person can seem dull and confused in the morning, barely able to follow a conversation or spell a word, and alert and interested at night, telling jokes and regaling listeners with details of some recent event?

Or, as Mucke so aptly states, “These rapid fluctuations are unlikely to result from suddenly losing neurons then gaining them right back. You can’t be both losing and gaining neurons. Plus, learning and memory loss in Alzheimer’s are not associated with [amyloid beta protein] plaque build-up. Something else must be happening to help people maintain a higher level of functioning.”

Now it seems that they do know what is happening. Amyloid beta protein triggers an abnormal excitation of brain cells, followed by an oversuppression of these same cells. The electrical whipsaw may underlie the mystifying, day-to-day – and sometimes hour-to-hour – changes in the disabilities of Alzheimer’s patients.

The good news? If researchers and drug developers can figure out a way to suppress the seizures or minimize its impact – and Mucke’s group has identified a strategy to do that in experimental Alzheimer's disease models – then it might be possible to prevent and even reverse cognitive impairments. Better yet, finding the right formula could protect against Parkinson’s and ALS too.

The not-so-good news? Science is a winding road with a lot of switchbacks. Progress takes time. Still, for those of us starting on our downhill slide, it’s encouraging to think that science might be there to help us put on the brakes.

That is, of course, unless we’re so obese that the brakes give out. With two out of three adult Americans now considered overweight, that possibility cannot be ruled out.

Now, we all understand that eating less and exercising more is the key to a healthy weight. But the scope of the problem is now so huge – and the health consequences so severe – that large-scale behavioral change and a new national commitment to prevention, assuming one arises, would still leave millions behind.

Science is stepping into that breach. And Robert Farese Jr., MD, senior investigator at the Gladstone Institute of Cardiovascular Disease and UCSF professor of medicine, biochemistry and biophysics, tantalized the “From Molecules to Medicine” mini-symposium audience with tales of how lipid droplets and fat storage are reshaping the debate.

In short, Farese and his Gladstone team have found that when they deactivate a particular gene called DGAT1 in mice, the mice can eat as much as before and lose about half of their body fat. How can this be?

“These mice have a 10 to 15 percent increase in energy expenditure. They have increased oxygen consumption and they are more insulin-sensitive,” says Farese. Or, to state it differently: “Their engines are running higher.”

Even more intriguing, preliminary studies suggest that the mice – protected as they are against fat storage – might live longer.

No wonder that drug companies are burning plenty of calories as they rush toward phase I clinical trials of a DGAT inhibitor.

All in all, a red-letter report from Gladstone scientists and a big leap forward for UCSF science.

Random Notes: We are still evaluating the rather limited choices for UCSF research, center and institute sites that carry the official UCSF web branding banner. Expect to learn the winner soon. Brian Shoichet’s Nature article was one of the 10 most frequently downloaded from that journal’s site in August. As we near the first anniversary of Science Café, I am happy to report that podcast downloads for previous stories have now passed 60,000.