Fall 2008 - Cleveland Clinic Lerner Research Institute

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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
Focusing on the patients of tomorrow FALL 2008Beyond the LimitsJay Alberts, PhD, Biomedical Engineering, had justcompleted a 450-mile weeklong bicycle ride across Iowato raise awareness of Parkinson’s disease (PD). Quite bychance, a PD patient on a tandem bicycle mentioned thatshe didn’t have Parkinson’s symptoms during the rideand that the tremor in her hand was gone afterward.Jay Alberts, PhDDr. Alberts’ curiosity was roused.Could exercise — specifically, “forcedexercise,” in which people are pushedbeyond their normal limits — betherapeutic for PD patients?The PD patient in Iowa had beenpaired with a rider who set a cadencethat was faster than what the patientwould have pedaled alone. Dr. Albertsused this as a starting point to see if such forced exercise wouldimprove motor function in other PD patients.physical activity — the manual tasks that range from buttoningshirts to tying shoe laces to handwriting. Dr. Alberts has beenworking on the project with Mark Lowe, PhD, Cleveland Clinic’sImaging Institute, and Micheal Phillips, MD, Section Headof Imaging Sciences in the Cleveland Clinic Department ofDiagnostic Radiology.“There’s an increase in activation after just one forced exercisesession. We’ve seen improvements remain for four weeks aftera patient stopped forced exercising,” Dr. Alberts said.“We believe driving of the central nervous system may benecessary to produce the underlying biochemical changes whichneed to occur to improve motor function,” he said. “The nextsteps are to understand the mechanisms underlying improvedfunction, what is the minimum dose necessary for improvementsto occur, are these effects long-lasting, and does forced exerciseof this kind slow the progression of Parkinson’s.”Most previous interventions using exercise allowed PD patientsto set their own exercise rates, which yielded mixed results. Dr.Alberts designed a tandem bicycle that measures and monitorspatients’ performance, power and pedaling rate. The bicycleforces PD patients to pedal at rates 40% to 60% faster thanthey can achieve on their own.The results have been promising.“One encouraging aspect is the improvement in motor functionin patients’ arms even though they’re only using their legs duringthe exercising. We’ve seen as much as a 35% improvementin motor function,” Dr. Alberts said. “This suggests that forcedexercise is impacting higher brain function and improvingcentral motor function.”Scans of PD patients’ brains show that exercise seems tostimulate the supplementary motor area of the brain, the regionthat controls general movement and governs 60% of our dailyThe image on the left is a scan of a PD patient’s brain priorto exercise. The image on the right shows the brain areasinvolved in constant, forced tasks involving the thumb andindex finger of the dominant hand. After exercise, it wasclear that additional motor regions — particularly thesupplementary motor area (in the circle) — were recruitedfor task performance. (Photos: Mark J. Lowe, PhD, Directorof High-Field MRI, Cleveland Clinic Imaging Institute)13
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Fall 2008 - Cleveland Clinic Lerner Research Institute

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