Research Awards

Funds Allocated to Alzheimer's Research:

2006-2007 Research Awards

2009 Research Awards:

• $10,000 Awarded to University of Pittsburgh, Graduate School of Public Health for "Brain Cholesterol & Alzheimer's Disease Pathology" study conducted by Dr. Nicholas Fitz.
  
  A prolonged high cholesterol/high fat diet has been associated with increased rate of Alzheimer’s disease and decreased memory later in age. However, no specific treatment has been suggested to lessen the negative effects of high fat/high cholesterol levels on memory and other symptoms of Alzheimer’s disease.
  
  The Liver X receptors are proteins found in all cell types and play an important role in transporting and regulating cholesterol levels. Since inadequate regulation of cholesterol, either through diet or genetic factors, contributes to Alzheimer’s disease, we examined the effect of Liver X receptor activators on Alzheimer’s disease-like symptoms in a mouse model fed normal and high fat/high cholesterol diet. Here we show that in a mouse model for Alzheimer’s disease, a high fat/high cholesterol diet provided for 4 months worsened the Alzheimer’s disease-like symptoms evaluated by behavioral and biochemical tests. To examine the therapeutic potential of Liver X receptor activators, the mouse model was fed high fat/high cholesterol diet supplemented with the Liver X receptor activator, T0901317 (T0).
  
  Our results demonstrate that this treatment causes a significant improvement of memory when compared to the mice fed only a high fat/high cholesterol diet. Moreover, the effects of T0 activator on cognition correlated with Alzheimer’s disease-like symptoms in our mouse model. We found a significant decrease in amyloid plaque load, insoluble A-beta, and soluble A-beta oligomers; all hallmark changes also observed in human patients with Alzheimer’s disease. The data presented here show that LXR activation even when combined with a high fat/high cholesterol diet has positive effects on the progression of the Alzheimer’s disease by decreasing memory loss and lessening other hallmark signs of Alzheimer’s disease.
  
  This research was published in the Journal of Neuroscience.
  
  
• $10,000 Awarded to Cornell University for "Increase Vascular Permeability Near Amyloid-Beta Plaques in Alzheimer's Brains" a study conducted by Dr. Christopher Schaffer.
  
  Alzheimer’s disease starts when a protein called A-beta accumulates to high levels in the brain and, as a result, clumps into damaging aggregates. These A-beta aggregates are toxic to brain cells and can disrupt brain function by directly injuring neurons. However, A-beta aggregates may also be damaging to blood vessels. Now researchers at Cornell University are testing the possibility that A-beta aggregates damage blood vessels and thereby decrease blood flow in the brain. If true, this would suggest an additional mechanism by which brain cells are injured in Alzheimer’s disease and open the door to the development of new therapeutics that block this pathway.
  
  Blood vessels in the brain are not simply pipes that carry blood into and out of the brain, they consist of living cells that carry out complex functions. A-beta aggregates may injure these blood vessel cells enough that they release chemicals that cause white blood cells to stick to the vessel walls. White blood cells are usually recruited during infections or injury to combat foreign bacteria or to clean up damaged tissue. While this response is exactly what the body needs to fight off infection, in Alzheimer’s disease this inflammatory process may get out of control and cause problems.
  
  Members of Prof. Chris Schaffer’s research group in the Department of Biomedical Engineering at Cornell University are now working to find out if this inflammation of brain blood vessels is happening in Alzheimer’s disease. They use two-photon microscopy to look into the brain of live anesthetized mice. This imaging techniques lets them see the smallest blood vessels of the brain and even measure blood flow in these tiny vessels. Because mice do not naturally get Alzheimer’s disease, they use transgenic mice, which have been genetically altered to have genes associated with inherited forms of Alzheimer’s disease. By using fluorescent dyes, they can see A-beta deposits and also white blood cells. Their images show that when white blood cells stick to the wall of small capillaries, they plug up the vessel and stop blood flow. While this process happens in a small number of vessels in normal mice, they find that about five times more vessels are plugged in Alzheimer’s mice as compared to normal mice. They suspect that neurons downstream of the blocked flow suffer as a result of the stopped blood flow because they are no longer receive sufficient oxygen and nutrients. This suggests that in addition to directly damaging neurons, Alzheimer’s diseases might be causing tiny strokes that can further injure neurons and make dementia worse.

2010 Research Awards:

• $30,000 Awarded to University of Michigan for The Roles of Metal Ions in Alzheimer's Disease study conducted by Dr. Mi Hee Lim.
  
  Alzheimer’s disease (AD) is a neurodegenerative, fatal brain disease with no cure. A hallmark of this disease is the accumulation of neurofibrillary tangles and amyloid-beta (Abeta) plaques. Mechanisms for formation of these misfolded proteins and their associations with AD pathology are not entirely understood, though the hypothesis that metal ions are involved in the assembly of Abeta aggregates and their neurotoxicity including generation of reactive oxygen species (ROS) as a source of oxidative stress has been emerging. Additionally, aberrant metal ion homeostasis in Alzheimer’s brains triggers deactivation of Abeta-degrading enzymes, accelerating Abeta deposition. These studies suggest that metal ions can induce Alzheimer’s neuropathology, but it still is unclear whether/how they are implicated in the progression of the disease.
  
  The goal is to establish the roles of metal ions in AD. The approach is to develop a new class of small bifuncitional molecules that can interact synergistically with Ab and metal ions, thereby, providing fine controls of Ab aggregation and ROS production. Our first-generation molecules have been rationally designed. Some of these compounds have been tested and have showed modulation of metal-induced Ab aggregation and neurotoxicity in cell-free solutions and in human neuroblastoma cells. These preliminary findings put us in position to generate a new class of small molecules and use these reagents as chemical probes to unravel metal-involved pathogenesis in AD and as potential therapeutic agents for metal-ion chelation therapy.
  
  
• $30,000 Awarded to University of California, San Diego for "Stress-Signaling Pathways & Alzheimer's Disease Pathology" led by Dr. Robert Rissman.
  
  Alzheimer’s disease (AD) currently afflicts five million Americans and is the most common form of dementia. It is definitely diagnosed by the presence of senile plaques and neurofibrillary tangle pathology in the postmortem brain. AD is thought to be caused by a toxic protein fragment, β-amyloid (Aβ) peptide which accumulates as senile plaques in the AD brain. Current FDA-approved drugs are not yet able to prevent or reverse AD, and provide only modest and temporary symptomatic benefits. New strategies focused on reducing Aβ accumulation in brain are a major focus for the next generation of potential treatment: disease-modifying therapies.
  
  The majority of AD cases are sporadic, of unknown origin. With this in mind, researchers are trying to identify environmental factors that may be involved in AD. Exposure to chronic stress is one factor that has been consistently implicated in age-related neurodegenerative disorders such as AD. Clinical research by scientists at Rush University in Chicago demonstrates that people who are more susceptible to stress are nearly three times more likely to develop AD.
  
  A forthcoming research project led by Dr. Robert Rissman at the University of California, San Diego is focused on the characterization of drugs that modulate the brain’s stress circuitry as a treatment for AD. Corticotropin-releasing factor (CRF) is a neuropeptide implicated in stress signaling at multiple levels, including many AD-related events. As an explanation for clinical studies demonstrating increased risk of AD with stress, data from Dr. Rissman’s lab has shown that stress exposure in rodents can induce the initial steps involved in neurofibrillary tangle pathology, and can also increases Aβ production. Recent research from Rissman’s team demonstrates that partial interference of CRF pathways in AD transgenic mice can also dramatically reduce Aβ levels. The goal of upcoming research is to use specific genetic and pharmacological tools to ascertain the intermediates and mechanisms of this effect, and to evaluate CRF-interfering drugs as a target for early intervention in AD.
  
  
• $40,000 Awarded to the Alzheimer's Association to co-fund "New Investigator Research Grant" to Anna Krichevsky, Ph.D., Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital (Boston, MA), for a research project titled "MicroRNA Regulation of Early Events in Alzheimer's Disease."
  
  Ribonucleic acids (RNAs) known as messenger RNA (mRNA) are important molecules that carry the genetic code from the genetic material (DNA) to the cellular machinery that makes proteins. Recently, however, a new kind of RNA has been described that performs a different function. These new molecules, microRNA, regulate which mRNA molecules are used to make proteins.
  
  Several lines of evidence suggest that microRNAs may play an important role in the development of Alzheimer’s disease. Anna Krichevsky, Ph.D. and colleagues have identified specific microRNAs that are expressed at abnormally high levels in the brain during the early stages of the disease. The researchers have proposed to study these microRNAs in detail in order to understand their normal function, and their contribution to the development of Alzheimer’s disease.
  
  Dr. Krichevsky and colleagues have found preliminary evidence that the microRNAs they have identified might alter the normally stable biochemical state of nerve cells. Evidence also suggests that microRNAs may increase the expression of amyloid precursor protein and tau, two proteins that form the characteristic pathologic features of Alzheimer’s disease. These studies may reveal previously unknown biochemical pathways leading to the development of Alzheimer pathology, and possibly suggest new therapeutic targets.
  
  
• $40,000 Awarded to the Alzheimer's Association to co-fund "New Investigator Research Grant" to Hyoung-gon Lee, Ph.D., Case Western Reserve University (Cleveland, OH) "Effect and Mechanism of Cell Cycle Re-entry in Neurodegeneration."
  
  Nearly all cells exhibit a cycle of growth in which cell division (when one cell divides into two new cells) alternates with periods of non-dividing activity. Nerve cells exhibit this cycle in early development, but then biochemical mechanisms turn off the cycle, allowing the nerve cells to form the unique structures and capabilities of the brain. There is some evidence, however, that nerve cells in the Alzheimer brain undergo biochemical changes causing them to attempt to return to the cycle of cell division. Unfortunately when mature nerve cells return to the cell division cycle, they die.
  
  At this time, it is not known whether return to the cell division cycle is the main cause of neurodegeneration in Alzheimer’s disease, or whether other biochemical changes are also involved. Hyuong-gon Lee, Ph.D. and colleagues are studying how nerve cells return to the cell division cycle and the role of that process in neurodegeneration. The researchers are focusing on a protein known as the retinoblastoma protein (Rb), which normally stops cells from dividing. There is evidence that this protein may be inhibited in the brain in Alzheimer’s disease. Therefore, Dr. Lee’s team has generated a mouse model that has been genetically altered so that the researchers can turn off expression of the Rb protein in one region of the brain. Using their mouse model, the researchers will determine if allowing nerve cells to return to the cell division cycle causes neurodegeneration. They will also examine if this effect produces the characteristic brain pathology seen in Alzheimer’s disease. These studies will help to address a fundamental question about the causes of nerve cell death in the early stages of Alzheimer’s disease, and they may suggest ways to prevent such cell death.
  
  

2011 Research Awards:

• $60,160 Awarded to University of Michigan for "Investigation of Small Molecules as Chemical Tools and Potential Therapeutics for Alzheimer's Disease." a study conducted by Dr. Mi Hee Lim.
  
  Dr. Lim’s research group is working to understand the role of metal ions in Alzheimer's disease, especially how metal ions are involved in the formation and aggregation of amyloid plaques in the brain, a hallmark of the disease. Previous reports have suggested that metal interactions with amyloid species are involved. These specific interactions lead to neuronal cell death and the generation of reactive oxygen species, which initiates oxidative stress. They plan to develop small molecules as chemical tools that can be used to study the interaction between amyloid beta plaques and metal ions. Not only will they be working on breaking up the plaque into smaller pieces (so that it can be removed from the brain), but they will also be focusing on preventing the amyloid plaque deposits from occurring.
  
  The majority of AAQI's funding for this project is for work which will be done by postdoctoral fellow Dr. Xiaoming He. He will be (a) testing in vitro blood-brain barrier permeability of newly designed bifunctional small molecules; (b) investigating in vitro activity of these compounds that can target metal-amyloid species and modulate metal-induced amyloid aggregation pathways and neurotoxicity; (c) exploring the cytotoxicity of the compounds in the absence and presence of metal ions and regulation of small molecules on neurotoxicity in living cells; and (d) studying influence of metal influx using the team's cpompounds on the up-regulation pathways of matrix metalloproteinases that can be responsible for amyloid clearance in the brain.
  
  
• $25,000 Awarded to the University of Pittsburgh for "Effect of Different Forms of ApoE on Treatment of Alzheimer's Disease," a study conducted by Dr. Nicholas Fitz.
  
  "Scientists show a link between cholesterol metabolism and Alzheimer's disease. ApoE is a critical protein in regulating the levels of cholesterol in the brain. Those expressing the APOE4 allele have a higher incidence of Alzheimer's disease compared to APOE3 carriers, and lower levels of ApoE4 protein. The APOE4 allele is the only proven genetic risk factor for Late-Onset Alzheimer's disease. We hypothesize that treating mice with compounds that influence cholesterol metabolism is a way to increase levels of ApoE protein, which may slow the progression of Alzheimer's disease. Furthermore, we believe that mice bred to express human ApoE3 and ApoE4 will respond differently to these treatments, emphasizing the need to develop treatments for Alzheimer's disease specific to different populations of patients." (Dr. Nicholas Fitz)
  
  
• $30,000 Awarded to the Cornell University for "Alzheimer's Disease Leads to Increased Blood Flow Stalls in Brain Capillaries," a study conducted by Dr. Chris Schaffer.
  
  "In the conventional view of Alzheimer’s disease it is thought that neurons in the brain are damaged by the accumulation of a small protein called amyloid-beta, but recent work shows that the blood vessels in the brain are also affected by amyloid-beta. In addition, Alzheimer patients have less blood flow in their brains than people without the disease. It is possible that the vascular effects of amyloid-beta and this blood flow decrease could contribute to the symptoms of Alzheimer's disease and add to the impact of the direct neuronal damage by amyloid-beta. Our work suggests that the blood flow decrease may be caused by white blood cells that block small blood vessels in the brain. Normally, white blood cells become activated, stick to the wall of blood vessels, then exit the vasculature and tissue in response to an infection or injury. However, in Alzheimer’s disease such activation may be detrimental because it could slow blood flow and deprive brain cells of oxygen and nutrients. In addition, the decreased blood flow may trigger the accumulation of more amyloid-beta, producing a vicious cycle of injury to the brain. In this work, we will test potential therapies that prevent the white blood cells from plugging blood vessels. We expect to see an increase in blood flow and hope to see a decrease in amyloid-beta accumulation. This work relies on new imaging techniques that enable us to track changes in amyloid-beta and blood flow with micrometer resolution in mice that are engineered to develop Alzheimer's disease. If successful, this therapy could potentially slow the progression of Alzheimer’s disease in patients." (Dr. Chris Schaffer)