Young Scientist Receives Boost to Explore Alzheimer’s Theory

Posted in GUMC Stories

APRIL 22, 2014 – Irfan Y. Tamboli, PhD , is a young neuroscience investigator with an intriguing theory of the origins of Alzheimer’s disease—getting at the fundamental question of why some people get it and others do not. He just needed a bump of support to pursue his hypothesis and see if it can stand up to further scrutiny.

Tamboli, a research instructor in the department of neurology, received that bump when he was named the recipient of a $25,000 grant from last year’s Music for the Mind . The annual event, now in its fourth year, supports young investigators at Georgetown University Medical Center (GUMC) who have bright ideas for seeking treatments and cures for neurological diseases.

Tamboli says early funding like this Music for the Mind grant is critical for budding scientists who are establishing their research focus. In his case, the grant will allow him to collect additional research data to test his theory about Alzheimer’s disease and hopefully to pursue additional funding down the line.

“We have many good ideas—and now we can get started on them,” he says.

The Hypothesis

Tamboli, who came to Georgetown in 2011 and has a background in molecular and cell biology and biochemistry, has long been fascinated with role of lipids, or fats, in health and disease.

As a PhD candidate in Bonn, Germany, Tamboli had the opportunity to work in a lab that is world famous for deciphering the effect of lipids on Alzheimer’s disease. He was eager to get in on the detective work.

Tamboli chose to look at APOE genes, which transport lipids in the brain. These genes are also the most prominent genetic risk factor for non-familial Alzheimer’s disease. The E4 form of APOE (APOE4) increases the risk of getting the disease by as much as eight fold. The E3 form of APOE (APOE3) is the most common variant, but appears to have a neutral role in the disease. The E2 form (APOE2), which is much more rare, appears to be protective against the disease.

Despite the known connection to the disease, it has never been clear what precise role APOE plays in neurodegeneration.

Tamboli thinks he has a strong clue. Working in the Georgetown lab of G. William Rebeck, PhD , professor of neuroscience, Tamboli has found that the APOE4 variant is less efficient at transporting lipids to brain cells than either APOE3 or APOE2. It seems that a protein called LRP1, a docking station on neurons for APOE, binds differently with APOE4.

“What we think is happening is that LRP1 does not bind in the same way to APOE4 as it does to APOE3 or APOE2. There is only one amino acid difference between the variants, but that can affect the ability of the cell to take in the lipid,” Tamboli says.

This matters, he adds, because lipids are critical structural and signaling molecules that serve many important functions inside the cell—including staving off cognitive decline. Cholesterol, a type of lipid, is essential to proper neuronal functioning; a malfunction in transporting and depositing cholesterol can damage neurons.

“If APOE4 is not efficient at depositing the lipids, then neurons will not get enough of the fats they are dependent upon. With time, we think that could lead to memory deficits and neurodegeneration,” Tamboli says.

Rebeck is enthusiastic about Tamboli’s hypothesis.

“He is testing whether this difference in APOE-neuron interactions makes the neurons more sensitive to damage that accumulates with aging,” he says. “Understanding why some people get Alzheimer’s and others don’t is one of the fundamental questions. The genetic predispositions give us an interesting place to start.”

A Look Ahead

Much has yet to be done to prove Tamboli’s theory, and that is where the Music for the Mind funds will come into play.

Tamboli plans to buy lipid particles made with different APOE compositions to reconfirm his initial findings that binding between APOE4 and LRP1 is altered. He then wants to look at lipid profiles in mice with either APOE3 or APOE4 in the brain. He hopes findings from these studies will lead to more research funding.

In endorsing Tamboli for the award, Howard J. Federoff, MD, PhD , professor of neurology and executive vice president for health sciences, says that moving the studies into mice models “can help investigators understand how they can mitigate plaque formation and reduce the occurrence of dementia.”

Music for the Mind this year will be held Wednesday, April 30, 2014, at Arena Stage in Washington. Click here for ticket information.

By Renee Twombly and Lauren Wolkoff
GUMC Communications