Fall 2008 - Cleveland Clinic Lerner Research Institute

Lerner research instituteGetting to the Heartof Alzheimer’sA few years ago, Jonathan Smith, PhD, Cell Biology, was studying how a particular gene helps to transportfatty compounds called lipids throughout the body. Lipids are a major contributor to the plaque that formson the inside of arteries that can lead to heart attacks or strokes, so learning how to control or reverse thisbuildup is a critical healthcare goal.Jonathan Smith, PhDThen Dr. Smith heard a bit ofinteresting news. The same genealso was found to be linked to thehallmark senile plaque that formsin the brains of patients withAlzheimer’s disease (AD). Couldhis work in cardiovascular geneticsalso contribute to AD research?The focus is on a gene calledapolipoprotein E, or ApoE for short. ApoE produces severalvariations of a protein — the protein helps to transport lipids andis linked to AD. The protein ApoE-ε3 is the most common form,while ApoE-ε2 and ApoE-ε4 are relatively common variants.“If you look at Alzheimer’s cases, about two-thirds of the patientscarry at least one copy of the gene that produces ApoE-ε4, whileonly one quarter of a young control population are ApoE-ε4carriers. People who carry one copy of ApoE-ε4 have a two- tofour-fold risk of AD, mostly among women. About 2% of peoplecarry two copies of ApoE-ε4, and they have a 15-fold risk ofAlzheimer’s,” Dr. Smith said. “It’s the most prevalent geneticsusceptibility factor for AD by far.”Although there is much to still be discovered about howApoE-ε4 plays a role in AD susceptibility, Dr. Smith’s ADresearch has shifted to looking for a drug that could preventor delay the onset of AD. A protein called amyloid precursorprotein produces a substance called beta-amyloid peptide (Aβ).Aβ is the major component of the plaque that forms in thebrains of Alzheimer’s patients.“By the time a person is diagnosed with Alzheimer’s, it’s toolate. Too much damage has been done,” he said. “The bestapproach is to work toward therapies that prevent or delay theage of onset of the disease. If you delay the age of onset by evenfive or 10 years, you could reduce the incidence of AD by halfand significantly improve the burden on patients and society.”To achieve this goal, Dr. Smith and his colleague EnakshiChakrabarti, PhD, Cell Biology, screened a library of smallmolecule compounds at the Institute’s Small Molecule ScreeningCore. Small molecules are small organic compounds that arebiologically active and can be used as “tools” in molecular biologyor as drugs in medicine. The goal is to find compounds that couldinhibit Aβ secretion from cells of the human nervous system.Although they have identified a compound of interest that isvery effective in reducing Aβ production, this drug does nothave the properties that will allow it to pass through theblood-brain barrier, a membrane that primarily protects thebrain from chemicals in the blood, while still allowing essentialmetabolic function.Dr. Smith is now working with Lawrence Sayre, PhD, a chemistat Case Western Reserve University, to modify this compoundso that it can enter the brain. Once a drug that can inhibit Aβproduction has been shown to be both safe and effective, aperson with a family history of Alzheimer’s or someone whocarries the ApoE-ε4 variant could start a daily drug regimen intheir 40s or 50s — something as simple as a daily pill — thatmight be able to prevent the disease.12