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.

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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