Alzheimer’s disease (AD) is thought to be caused in part by the build-up of amyloid beta (Aβ) protein in the brain. Although the basic process that generates Aβ is well studied, an important unresolved question is what factors turn this process on and off. We have identified for the first time serine/threonine-protein kinase PLK2, an enzyme that in humans is encoded by the PLK2 gene, as a candidate factor that stimulates Aβ production. Here we will examine the role of PLK2 in disease progression using mouse models of Alzheimer's. These studies are critical for understanding the mechanisms underlying Alzheimer's and for advancing new targets for drug therapies.
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- Daniel Pak, PhDGeorgetown University (Washington, DC)ID:A2017508SJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$300,000
- Tao Ma, MD, PhDWake Forest University School of Medicine (Winston-Salem, NC)
The basic causes underlying the cognitive deterioration in Alzheimer’s disease (AD) and other dementias remain elusive, which hampers the development of any effective therapies. This project will shed light on whether new proteins synthesized in association with a cellular signaling factor (eEF2K/eEF2 signaling) play a role in AD pathogenesis This work could inform future identification of novel diagnostic markers and therapeutic targets for AD and related cognitive syndromes.ID:A2017457SCollaborators:Christina M. Furdui, PhDJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$300,000
- Majken Jensen, PhDHarvard University (Boston, MA)
Diet plays an important role in the development of many chronic diseases. However, we still don’t have a good understanding of which dietary components are most important for the prevention of Alzheimer’s disease (AD). In this project, we will identify key healthy dietary patterns that can form the foundation of dietary recommendations to lower Alzheimer’s risk. This is important because diet is among the risk factors that are modifiable; thus we can change our behavior and lower our risk of this devastating disease.ID:A2017290SJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$297,818
- Philippe Mourrain, PhDStanford University (Stanford, CA)
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world but its genetics is still unclear. Most of the DNA variations in AMD patients are found outside of the genes, and it is extremely hard to know whether these variants are actual mutations and what genes they affect. We have found that some of these variants are located in genome regions conserved down to the zebrafish, and surrounded by the same neighborhood of genes as in the human genome. Their preservation in the zebrafish allows us to visualize in this transparent genetic vertebrate model whether these variants are just neutral or if they disrupt the regulation of one the neighbor genes, possibly revealing the actual gene affected in AMD human patients.ID:M2017209Co-principal Investigators:Romain Madelaine, PhDCollaborators:Jeffrey Goldberg, MD, PhD; Douglas Vollrath, MD, PhDJuly 1, 2017 to June 30, 2019Macular DegenerationStandard$160,000
This grant is made possible by support from the Nancy Ferguson Seeley Trust in memory of Mildred F. Ferguson.
- Sarah Fritschi, PhDWashington University School of Medicine (St. Louis, MO)
Sleep problems, such as wakefulness at night and daytime napping, are common in patients with Alzheimer disease (AD). While sleep disturbances are often considered to be a consequence of neurodegeneration, we are taking another look. Data suggest that sleep disturbances occur very early in the course of the disease and might possibly contribute to AD-associated pathologies as well as the onset of cognitive symptoms including mild cognitive impairment (MCI). By switching sleep on and off, we will be able to assess whether sleep disturbances, such as unusual sleep duration and sleep fragmentation, are an early factor that contributes to the risk of developing AD.ID:A2017114FMentors:David M. Holtzman, MDJuly 1, 2017 to September 30, 2018Alzheimer's DiseasePostdoctoral Fellowship$100,000
- Lea Grinberg, MD, PhDUniversity of California, San Francisco (San Francisco, CA)
For screening and clinical management, and for clinical trials, it would be extremely useful to be able to monitor the pathological progression of Alzheimer’s disease (AD), especially during the decades preceding the onset of clinical symptoms when AD spreads silently in the brain. To date, postmortem examination remains the only tool to confirm and stage AD diagnosis. We found that a tiny brainstem nucleus, the locus ceruleus (LC), is especially vulnerable and earliest-damaged in AD. Furthermore, investigating postmortem tissue, we found evidence that in AD patients, the LC showed linear and progressive shrinkage. We will develop a histologically-validated clinical MRI [magnetic resonance imaging] template for detecting LC shrinkage. This should allow us to track AD progression on a case-by-case in individuals and permit intervention before a substantial amount of neurons have died. LC volumetry is potentially more scalable and economical than other potential AD biomarkers, and could be developed for longitudinal screening. Having such a method in place would in turn make it more feasible to identify and triage high-risk candidates for less accessible, more expensive, and more invasive studies, including PET [positron emission tomography] scans and spinal taps.ID:A2017560SCollaborators:Edson Amaro Jr., MD, PhD; Helmut Heinsen, MD, PhD; Duygu Tosun, PhD; Daniela Ushizima, PhDJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$300,000
This grant is made possible in part by support from The Carl and Judy Moore Charitable Foundation.
- Esther G. Gonzalez, PhDKrembil Research Institute (Toronto, Canada)
Glaucoma is known as the “silent killer of vision” because a large proportion of people are not aware they have it until the late stages of the disease, and therefore it is very important to detect the disease early so these patients get help. It is also important to understand the disease in order to develop new lines of treatments. There are new indications that changes occur not only in the eyes but also in the brain of these patients, particularly in a structure that connects the two brain hemispheres. We plan to study the function of this brain structure in humans with glaucoma using a series of non-invasive tests.
This grant was transferred to Dr. Esther G. Gonzalez upon the passing of the original PI, Dr. Martin Steinbach in June 2017. The research project is being continued in Martin's memory.ID:G2017093July 1, 2017 to June 30, 2019GlaucomaStandard$150,000
- Chaeyoung Kim, PhDGladstone Institutes (San Francisco, CA)
Apolipoprotein E (apoE) has important roles in both normal central nervous system physiology and neuropathology, such as Alzheimer’s disease (AD). Importantly, the apoE4, one of apoE isoforms, is the major genetic risk factor for AD, and generates toxic fragments that cause mitochondrial dysfunction and drive neurodegeneration. Because mitochondrial dysfunction and metabolic impairment are critical elements of AD pathology, I will study how apoE4 and its neurotoxic fragments interact with mitochondria and alter mitochondrial activity. This largely unexplored approach will provide insight into the mechanisms underlying the role of apoE4 in AD and may identify new therapeutic targets to treat apoE4-associated AD.ID:A2017214FMentors:Robert W. Mahley, MD, PhDJuly 1, 2017 to June 30, 2019Alzheimer's DiseasePostdoctoral Fellowship$100,000
- Randy McIntosh, PhDBaycrest Centre for Geriatric Care (Toronto, Canada)
The brain is a complicated system whose different parts interact to support a variety of cognitive functions. This complexity makes it difficult to treat diseases such as Alzheimer’s and Parkinson’s, where many different brain areas can be affected, but lead to very similar deficits, such as memory dysfunction. Our research provides a framework of tools to “reconstruct” the brain and build models of different dementias to characterize the unique features of each disease and the final common paths to cognitive impairment. As our work progresses, it will be used to evaluate the potential of therapeutic interventions to help identify treatment targets, or areas of the brain that, if treated, are most likely to result in the best outcome for the individual.ID:A2017286SCo-principal Investigators:Kelly Shen, PhDCollaborators:Michael Breakspear, PhD; Viktor Jirsa, PhD; Petra Ritter, PhD; Ana Solodkin, PhDJuly 1, 2017 to June 30, 2020Alzheimer's DiseaseStandard$299,565
- Krishnakumar Kizhatil, PhDThe Jackson Laboratory (Bar Harbor, ME)
Glaucoma is a devastating neurodegenerative disease that causes blindness. Glaucoma results from increased pressure in the eye; however, the mechanistic basis of the pressure increase is largely undetermined. Neurons innervating the eye play a role in controlling pressure, but again the specific mechanisms are not clear. We will determine the mechanistic basis of neuronal control of eye pressure using mice and modern imaging and molecular methods.ID:G2017152Collaborators:Simon W. M. John, PhDJuly 1, 2017 to June 30, 2019GlaucomaStandard$150,000