AAQI Research Awards

Funds Allocated to Alzheimer's Research:

2006-2007 Research Awards

$157,595.50 donated to various chapters of the Alzheimer’s Association as restricted donations to research. (Before incorporation as a nonprofit.)

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 technique 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 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 compounds 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)

  • $30,000 Awarded to the University of Michigan for "Development of Multifunctional Drugs for Alzheimer's," a study conducted by Dr. Sylvie Garneau-Tsodikova.

    "Alzheimer’s disease (AD) is a complex neurodegenerative disorder of the central nervous system. Even though the exact cause of the disease remains unknown, several pathological hallmarks of AD have been identified. Examples of these hallmarks include (i) decreased levels of cholinergic neurons and neurotransmitter acetylcholine, (ii) the formation and aggregation of amyloid-beta plaques in the brain, (iii) inflammation and increased oxidative stress from reactive oxygen species, and (iv) the presence of metal ions such as copper and zinc that interact with the amyloid-beta plaques. Even though all of these hallmarks are interconnected and should be taken into consideration when designing novel drugs for the treatment of AD, most of the currently approved therapies are centered on only one of the problems associated with the disease, the decreased levels of the neurotransmitter acetylcholine. In this work, we propose to design, synthesize, and test novel small molecules that will simultaneously target all of the four hallmarks of AD described above. We expect that with their multifunctional properties our compounds will better be suited to combat this devastating multifactorial disorder."

    2012 Research Awards:

    • $60,000 Awarded to the Temple University for "Corticosteroids, 5Lipoxygenase & Alzheimer's Disease," a study conducted by Dr. Domenico Praticň.

      AD is characterized by the deposition of Amyloid Beta peptide (amyloid plaques) and neurofibrillary tangles (NFTs) composed of tau protein in the brain. Though it is incompletely understood how they cause the cognitive deficits seen in AD, a large body of evidence suggests that Aβ plays a central role. However, while only a minority of AD cases is caused by mutations in genes involved in the formation of Amyloid Beta, the cause of sporadic AD, which represents 95% of all cases, remains unclear, and several environmental risk factors have been invoked.

      Recent clinical investigations have implicated adverse psychosocial stress as one important environmental risk factor to develop AD. Thus, psychological stress exacerbates AD symptomatology, increased plasma corticosteroid levels are reported in patients with AD, and they correlate with a more rapid cognitive decline. Glucocorticoids are known to alter many functions of the brain. Among a variety of biological effects, glucocorticoids increase the expression of a protein called 5Lipoxygenase (5LO) in the neurons. Recently we have learned that this protein in the brain functions as a regulator for the formation of the Amyloid beta inside the neurons.

      Thus, while there is evidence that suggests that glucocorticoids and 5LO, separately, are involved in AD pathogenesis, there has been no work so far that attempts to simultaneously link them to AD. The proposed work will establish the link between 5LO and stress hormones in AD by looking not only at the influence on Aß and NFT-associated brain pathology, but more critically studying the cognitive aspects.

      Successful accomplishment of our study will form the basis of a readily-translatable therapeutic strategy, because 5LO inhibitors are safe and FDA-approved for use in other chronic diseases and would be highly beneficial in treating individuals with this environmental risk factor who are at higher risk to develop AD."
      (Dr. Domenico Praticň)

    2013 Research Awards:

    • $40,894 Awarded to Texas A & M Health Science Center for "Amyloid cross-seeding as a mechanitstic link between diabetes and Alzheimer's disease," a study conducted by Dr. Ian V. J. Murray and Dr. Carmen Ramirez.

      Alzheimer's disease (AD) currently affects 5.4 million people with the number predicted to double by 2050, and there is currently no cure. AD pathology occurs decades prior to clinical diagnosis and thus it is important to identify factors that contribute to the pathology to develop strategies to prevent it.

      Type 2 diabetes is one factor that increases the risk of Alzheimer’s disease, although not everyone with diabetes will get Alzheimer’s. Dr Murray and Ramirez are proposing a novel mechanism that potentially explains this link. This research represents collaboration between a basic science researcher (Dr Murray) and a clinician (Dr Ramirez).

      They hypothesize that the association between metabolic dysfunction and AD is due to a pancreatic protein. They propose that elevation of this protein in the early stages of type 2 diabetes results in more entering the brain and accelerating the clumping of a toxic protein (amyloid ). This could potentially accelerate the development of Alzheimer’s disease in susceptible persons.

      Their preliminary data in animal models and samples from Alzheimer’s disease patients supports this hypothesis. This grant by the AAQI will allow them to further test this hypothesis, as well as publish the resulting findings.

    • $35,000 Awarded to The University of Texas Medical Branch at Galveston for "Protective mechanisms against Alzheimer's disease dementia," a study conducted by Dr. Nicole L. Bjorklund.

      Nicole Bjorklund, Ph.D., a postdoctoral fellow in Dr. Giulio Taglialatela’s lab in the Neuroscience and Cell Biology Department at the University of Texas Medical Branch in Galveston, TX, has been focused for the last three years on discovering how some individuals are able to evade dementia despite having the pathological signs of Alzheimer’s disease found upon autopsy. In their recently published paper in Molecular Neurogeneration, they report that the toxic protein, amyloid beta – the protein found in plaques in the brain of Alzheimer’s disease patients, did not attach to the synapses of the dementia-free individuals. This is important because synapses are the communication hot spots in our brains. The proper functioning of synapses is absolutely required for learning and memory formation. This means that the dementia-free individuals with the pathology of Alzheimer’s disease are naturally able to resist cognitive decline.

      The project funded by the Alzheimer’s Art Quilt Initiative will help understand this dementia-fighting mechanism. The current project will focus on the composition of synapses of a cohort of individuals that did not suffer from dementia until very late age. This group was able to resist dementia far longer than most individuals with this disease. We hope to further understand how some individuals can fight dementia naturally. The examination of these specimens will lead us to understanding mechanisms that can resist dementia and that can work in the human brain.

    • $38,354 Awarded to Johns Hopkins University, Bloomberg School of Public Health for "Bfk, a novel mediator of neuronal death in Alzheimer's disease," a study conducted by Dr. Lucian Soane.

      Late stages of Alzheimer’s disease (AD) are characterized by loss of neurons in the brain, but the mechanisms involved are not fully understood. A class of enzymes, called cathepsins, have been long suspected as culprits and new evidence supports this idea. Although inhibition of these enzymes has been proposed as therapeutic strategy in AD, cathepsins have important physiologic roles and their inhibition may have unwanted effects. Therefore, targeting of cell death-inducing molecules activated by cathepsins may be more beneficial. However, the substrates of cathepsins that are responsible for inducing neuronal death are still unidentified. While studying the mechanisms of neuronal death we identified Bfk, a poorly characterized protein that belongs to a family of cell death regulators, as a new target of cathepsins. Our studies revealed that when activated by cathepsins this protein becomes a potent death-inducer in brain cells. We will investigate here whether this protein is the previously unidentified mediator of neuronal death in AD brains in response to amyloid beta. This is the first study to address this hypothesis and could potentially lead to identification of a new target for Alzheimer’s disease therapy.

    • $60,000 Awarded to Mt. Sinai School of Medicine, for "Metabotropic glutamate receptors in Alzheimer's disease," a study conducted by Dr. Michelle E. Ehrlich.

      Research into potential treatments of Alzheimer’s disease (AD) has moved largely from treatment to prevention. We have identified a drug compound that is potentially useful in both phases. Part of the problem in Alzheimer’s disease is that a sticky substance called amyloid disrupts communication between nerve cells. Ultimately, these nerve cells become sick and eventually die. The drug that we are testing in mouse models of AD has two functions which could potentially prove beneficial. First, it affects the pathway via which amyloid is made, and may help to decrease the amount of amyloid and thereby improve communication between nerve cells. Second, it increases the “birth” of new nerve cells, something which normally occurs only at a very low rate in the aged brain. We plan to administer this compound to mice that have been engineered to overproduce amyloid and that we have shown develop memory problems in tests specifically developed for mice. We hope to show that by decreasing the level of amyloid and simultaneously increasing the birth of new nerve cells, that this compound will improve the condition in the mice. This drug is being tested in humans for other conditions, so we hope that if there is a promising result in mice, that it can then be tested in AD patients.

    • $75,000 Awarded to Temple University, for "Five lipoxygenase and Alzheimer's disease related to tao pathology," a study conducted by Dr. Jin Chu.

      Alzheimer's disease (AD) is a progressive brain disorder that damages and eventually destroys brain cells, leading to memory loss and changes in thinking and other brain functions. It usually develops slowly and gradually gets worse as more brain cells wither and die. One of the most important abnormalities in the AD’s brain is the presence of particular deposits called tangles which are made of twisted microscopic strands of the protein tau. Tau protein is responsible for influencing the architecture of the neurons, as well as their function. When Tau does not function properly, it has a tendency to clump and precipitate and as results from tangels. Interestingly these precipitates are also present in other disease of the brain called tauopathies.

      Inflammation of the brain tissue is a process detectable in the earliest stages of AD and tauopathies. Much evidence suggests that alterations in inflammatory processes could be responsible for the formation of tau precipitates (tangles), but the mechanism involved is not clear yet.

      The 5Lipoxygense (5LO) is a pro-inflammatory enzyme widely expressed in the central nervous system. Previously, we reported that 5LO regulates â-amyloid protein (Aâ) levels and deposition in a transgenic mouse model of AD. In a more recent paper, we observed that 5LO also modulates the development of abnormal tau (tangles) and memory deficits of another mouse model. Taken together these data support our novel hypothesis that 5LO is a regulator of tau function, and for this reason a possible therapeutic target to prevent tau pathology and lesion development.

      To prove it we will investigate the contribution of 5LO to the development of age-dependent impairment of cognitive function, formation of abnormal tau in transgenic mice, which develop tau pathology features similar to those present in human AD. Additionally, by administering them a drug that specifically blocks the 5LO.

      If we demonstrate that pharmacological blockade of 5LO indeed prevents or reduces the formation of tangles, our results will form the basis of a readily-translatable therapeutic strategy, because 5LO inhibitors are safe and already FDA-approved for use in other chronic diseases, which could be beneficial in treating individuals not only with AD but with tauopathies.

    • $60,560 Awarded to Boston University Medical Center, for "Exosome-mediated dissemination of tau aggregation in Alzheimer's," a study conducted by Dr. Tsuneya Ikezu.

      Alzheimer’s disease (AD) pathology is characterized by the deposition and aggregation of two proteins in neurons: amyloid plaques and neurofibrillary tangles. Tangle pathology spreads in the brain from a specific cortical area to subcortical area in a stereotypical manner, and the pathology is well associated with disease symptoms. However, no specific mechanism is identified to understand or prevent the spreading of tangle pathology for the treatment of Alzheimer’s disease.

      Microglia are brain resident phagocytes (ingesting cells) that play important roles in the maintenance and inflammation in the central nervous system (brain and spinal cord). We found that microglia ingest aggregated tangle-forming tau proteins and can secrete them in small vesicles called microvesicles. Microglia are also found in the tangle-bearing brain regions, and associated with inflammation in AD brains. We hypothesize that microglia may mediate the spreading of aggregated tau protein via phagocytosis and secretion of small vesicles.

      Members of Prof. Tsuneya Ikezu’s research group in the Departments of Pharmacology and Experimental Therapeutics and Neurology at Boston University are doing experiments to figure out how microglia can engulf tangles from neurons, and how the tangles are seeded to neurons. They use primary cultured microglia and neurons and molecular biological approaches to identify the key molecules regulating the microglia-mediated secretory pathway in vitro and verify the findings obtained from the in vitro study by various histopathological technologies using human brain specimens.

      Successful completion of the study will provide a new therapeutic target for the treatment of Alzheimer’s disease, since suppression of the spreading of tau aggregation will prevent the formation of neurofibrillary tangles, which is closely associated with clinical symptoms.