The intelligent typology hypothesis of late onset Alzheimer’s disease: early failure in vascular graph fitness driven by impaired endothelial calcium dynamics

Investigators: Jonghwan Lee, associate professor of engineering and brain science, and Chris Moore, professor of neuroscience and brain science

Lee, an expert on imaging and analysis of brain microvasculature, has discovered that mice with the leading genetic risk factor for Alzheimer’s disease, APOE4, have vascular systems that look strikingly different from the vascular systems of normal mice. These differences have potential both for early diagnosis and as a therapeutic target, since they manifest much earlier than the disease onset and may have etiological roles in later pathological hallmarks of the disease. Here, he teams with Moore, an authority on various biological roles of microvasculature, to test a new novel hypothesis regarding the origins of this change. Through the innovation award, the team will use the latest imaging techniques, lab-built deep learning networks and graph theory to test their hypothesis that the gene APOE4 causes these vascular differences. “If our hypothesis proves correct, this opens up a totally new area of focus for Alzheimer’s disease research as well as a new suite of techniques that enables researchers to study it,” said the team. 

Discovering and interpreting novel biomarkers of Alzheimer’s disease progression in longitudinal MEG data

Investigator: Stephanie Jones, professor of neuroscience

Magnetoencephalography (MEG) is a noninvasive device that measures the magnetic fields produced by the brain’s electrical signals. The Jones Lab is on the cusp of being able to predict, by interpreting MEG data, whether or not a patient presenting with symptoms of mild cognitive decline will advance to Alzheimer’s disease two and a half years later–an incredibly complex computational feat. The innovation award will allow Jones and her team to hone their technique while working with a massive longitudinal MEG dataset comprising the results of hundreds of patients over multiple years, provided by her collaborators at the University of Madrid. “Refining the predictive power of our technique has the potential to turn magnetoencephalography from a purely diagnostic tool into one that can be used to actively diagnose and treat patients with symptoms of cognitive decline. Our ultimate goal is to delay or prevent progression to Alzheimer’s disease,” said Jones.

Defining the role of the hypothalamic-pituitary-ovary axis in the initiation and progression of Alzheimer’s disease

Investigator: Gregorio Valdez, GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry, Richard Freiman, professor of molecular biology, cell biology and biochemistry and professor of obstetrics and gynecology

Women are twice as likely to develop Alzheimer’s disease, but the reasons for this are understudied. Through an innovation award granted two years ago, Freiman and Valdez made a breakthrough: in female mice with Alzheimer’s disease, the ovaries, pituitary gland and hypothalamus weren’t communicating with each other like they normally would. Now, the team will use this new innovation award to explore whether the disruption of endocrine signaling between the ovary, pituitary and hypothalamus may be a helpful predictor of Alzheimer’s disease. In addition, by studying female mice with the premature onset of menopause, they will determine if any symptoms of Alzheimer’s disease appear earlier than expected. “Outcomes of this research will potentially identify new predictive biomarkers related to Alzheimer’s disease, but also may reveal new targets for therapeutic interventions that block or slow progression of the disease in women,” said the team. 

The role of retrotransposon activation in the etiology of Alzheimer’s disease and related dementias

Investigators: John Sedivy, Hermon C. Bumpus Professor of Biology, and Sukanta Jash, assistant professor of molecular biology, cell biology and biochemistry (research)

Retrotransposons are viral-like DNA sequences found throughout the human genome that are largely benign in healthy young individuals but, during diseases like Alzheimer’s, can become active and, like viruses, promote inflammation. Retrotransposons are related to the human immunodeficiency virus (HIV), and a few years ago Sedivy, an expert in this area, proposed that their inflammatory effects in Alzheimer’s disease could be targeted with drugs developed to treat HIV. An important missing link has been a test that could show that these drugs were controlling retrotransposons in patients. Through the innovation award, Sedivy and Jash, an expert on stem cells and RNA vaccine technologies, are teaming up to develop such a test. “If successful, this project will develop tools to enable researchers to determine whether drugs, either repurposed HIV drugs or completely new ones, are hitting and controlling the intended target. Those tools will also be critical for eventual FDA approval,” said the team.
 

Drug discovery for the prevention and treatment of Alzheimer’s disease

Investigators: Robbert Creton, professor of medical science (research), and Jill Kreiling, associate professor of molecular biology, cell biology and biochemistry (research)

There is an urgent need for more rapid preclinical testing of a novel class of Cyclosporine A type drugs, a recently discovered class of drugs that researchers believe may have applications for preventing and treating Alzheimer’s disease. Creton, Kreiling and their labs will study the impact of these drugs on 3D cultures of human neural stem cells engineered to form amyloid plaques and tau tangles, the proteins believed to negatively affect neurons in Alzheimer’s disease. To analyze their results, the team will utilize custom-developed high-throughput methodologies for imaging, automated image analysis and analyses of complex signaling networks. “This project is too risky for external funding at this time because Cyclosporine A type drugs have not been tested in preclinical Alzheimer's models. However, once we show that these drugs work in human neurons, it will be very appealing because Cyclosporine A type drugs are already in use for other conditions and may be repurposed as therapeutics for Alzheimer's disease," the team explained.

Metabolomic profiling in the locus coeruleus during stress and neurodegeneration

Investigator: Eric Morrow, Mencoff Family Professor of Biology and Director of the Center for Translational Neuroscience 

As the primary source of noradrenaline for the brain, the locus coeruleus is a neuromodulatory system regulating cognition, sleep and other behaviors. Pathology in the locus coeruleus is also one of the earliest events in Alzheimer’s disease, preceding and correlating with cognitive decline. The Morrow Lab will study a newly discovered metabolic pathway governing early locus coeruleus vulnerability that is relevant to Alzheimer’s disease and sleep. “If successful, our work will build a foundation for the development of inexpensive, widely-accessible, nutritional supplements that promote locus coeruleus health, and thereby may delay or prevent neurodegeneration,” said Morrow.

Development of a dual-bead-based immunoassay for the detection of Alzheimer’s disease biomarkers in neuronal-derived extracellular vesicles

Investigator: Anubhav Tripathi, professor of engineering, professor of biology and medical sciences

Researchers are able to screen neuronal-derived extracellular vesicles, particles that are naturally released from neurons and which are found in most biofluids including blood, for Alzheimer’s disease biomarkers. However, there is currently no method for screening extracellular vesicles for Alzheimer’s disease biomarkers quickly enough and at a high enough volume to make it a practical way for diagnosing patients. Through the innovation award, the Tripathi Lab will develop a dual-bead-based immunoassay for the detection of Alzheimer’s disease biomarkers in neuronal-derived extracellular vesicles. The lab has already developed an ultrasensitive method of protein detection and quantification for amyloid-beta, one of the proteins believed to negatively affect neurons in Alzheimer’s disease. Next, they will develop a multiplex capability and automate the process of sample preparation and cleaning. “We hope that our platform not only has a higher sensitivity than current methods of biomarker detection, but that it can provide a more user-friendly and cost effective solution for blood sample analysis. We are focusing on lowering the amount of sample required for the analysis of extracellular vesicles, which should increase turnaround time and provide patients and their families with faster results,” the team said.

Defining the contribution of ovaries to the onset and progression of Alzheimer’s disease

Investigators: Richard Freiman, professor of molecular biology, cell biology and biochemistry, professor of obstetrics and gynecology, and Gregorio Valdez, GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry (MCB) and Co-Director of the MCB Graduate Program

Women are twice as likely to develop Alzheimer’s disease as men. Yet, there is a dearth of information about the relationship between female sex characteristics and the onset and progression of the disease. Freiman and Valdez will run an integrative series of pilot studies with mice to define whether changes in the ovary contribute to the onset and progression of Alzheimer's disease. One group of experiments will examine the ovaries prior to, at the onset and during the progression of pathology in diverse mouse models of Alzheimer’s; the other group will examine the onset and severity of Alzheimer’s in mice with and without healthy ovarian functions. By studying the integration of the brain and ovaries, their project will not only contribute to potential therapeutic opportunities that prevent or slow a devastating neurodegenerative disease in women, but it will also address the imminent need to improve health-related research inequities between women and men. 

Sleep in adolescents at genetic risk for Alzheimer's Disease: a missing link to early life detection

Investigators: Jared Saletin, assistant professor of psychiatry and human behavior, and Mary Carskadon, professor of psychiatry and human behavior

Saletin and Carskadon seek to test an intriguing new possibility: whether alterations in brain and behavioral sleep-related mechanistic markers are already present early in life in adolescents at genetic risk for Alzheimer’s disease. Although adolescence is too early to express symptoms or visible plaques, early life consequences of the gene APOE4 have been observed in sleep-related phenotypes including hippocampus structure, memory and IQ. Thus, early changes in sleep — and potentially in brain makers of sleep-related glymphatic flow — may occur in at-risk youth. If findings in Saletin and Carskadon’s pilot project support this premise, they will open the door for early sleep-focused intervention long before Alzheimer’s symptoms emerge. 

Bioengineering hybrid cortical microtissues to study morphofunctional and transcriptional dynamics of human microglia in Alzheimer’s disease

Investigators: David Borton, associate professor of engineering, and Alvin Huang, GLF Translational Assistant Professor of Molecular Biology, Cell Biology and Biochemistry

In this project, Borton and Huang join forces to craft a new generation, stem cell-based tool for studying the immune responses unique to the human brain. Their goal is to make discoveries that will benefit researchers’ understanding and the treatment of a group of cumbersome brain disorders, including Alzheimer's disease. This novel tool is cost-effective and can be easily disseminated in the science community to speed up the development of new treatments, the researchers said.

Discovering novel biomarkers of aging and cognitive decline in large-scale open access human MEG data

Investigator: Stephanie Jones, associate professor of neuroscience

The neuroscience community is experiencing a revolution in its ability to share and analyze vast amounts of human brain imaging data. One domain in which there has been significant open access progress is magneto and electro-encephalography (M/EEG), where data is available from hundreds of subjects during resting states, various behavioral conditions and across the lifespan. In this project, scientists will apply novel temporal-spectral waveform classification methods to open-access MEG data to identify new biomarkers of age, gender and cognitive ability.

This biomarker identification, Jones said, will in turn provide targets for interpretation of the underlying neural mechanisms with the Jones Lab’s Human Neocortical Neurosolver computational neural modeling software. This project can help transform M/EEG from being purely diagnostic to providing targeted circuit interpretation that can guide treatments to improve brain function during cognitive decline with aging, Jones said. 

Discovery and validation of novel XPO1 inhibitors to prevent Alzheimer’s disease

Investigator: Louis Lapierre, assistant professor of molecular biology, cell biology and biochemistry

Members of the Lapierre Lab are investigating new modulators of nucleo-cytoplasmic protein partitioning that can improve global protein stability and enhance the rejuvenation process of autophagy in the brain. Autophagy is the degradation of cells, which removes damaged or unnecessary cellular components. Using newly-designed compounds in cells and murine models of Alzheimer's disease, Lapiere said he hopes to pharmacologically validate this approach in order to ultimately improve the clinical outcome of this disease.

Optimizing housing conditions to accelerate the translation of research using mouse models of Alzheimer's disease

Investigators: Gregorio Valdez, GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry, and Lalit Beura, assistant professor of molecular microbiology and immunology

Microbial exposure and the ensuing immune response play important roles in the incidence and progression of Alzheimer’s disease. Yet, scientists continue to study this disease in mice reared in ultra-hygienic, pathogen-free environments and consequently with a muted immune system, the researchers said. In this project, Valdez and Beura will study mouse models of Alzheimer’s disease exposed to naturally occurring pathogens and with a matured and heightened immune system. This innovative approach can accelerate the translation of discoveries made in animals to treat humans with Alzheimer’s disease, the researchers said.

Promoting adult hippocampal neurogenesis as a potential therapeutic for Alzheimer’s disease: In vivo testing of a novel target

Investigators: Justin Fallon, professor of medical science and of psychiatry and human behavior, and Ashley Webb, Richard and Edna Salomon Assistant Professor of Molecular Biology, Cell Biology and Biochemistry

Alzheimer’s disease is characterized by the loss of connections between nerve cells and ultimately neuronal death. Fallon and Webb have discovered a novel signaling pathway that promotes the birth of neurons in the adult brain and their integration into the mature circuitry. In this new project, they will test whether targeting this pathway boosts the formation and connectivity of new neurons in mouse models of Alzheimer’s disease.

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