The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain is pleased to announce the 2023 awardees of the TIGER pilot grant program for projects focusing on the neurobiology of aging and dementia, including Alzheimer's disease. These grants, which range in funding from $75,000--$200,000 per year, represent a dedicated mechanism to encourage and support innovative investigative ideas that require initial funding to gather sufficient data for obtaining external funding. Please view the full TIGER RFP for additional details.

Please join us in congratulating the 2023 TIGER Awardees (listed alphabetically by Contact PI):

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Recently, a newly identified highly prevalent condition known as LATE-NC has been linked to dementia in the elderly population. LATE-NC can coexist with AD, however, unlike AD, our understanding of LATE-NC remains limited. Currently, we lack reliable methods to diagnose LATE-NC during a patient's lifetime, and we can only make the diagnosis at the time of brain autopsy. In this project, we will address a fundamental question about the underlying mechanisms of brain damage in LATE-NC: How does LATE-NC impact various cells and regions of the brain? Answering this question will enhance our understanding of LATE-NC and allow us to develop tests that can potentially improve diagnosis and, hopefully, treatment. To investigate our questions, we will analyze brain tissue from individuals who generously donated their brains for research and were diagnosed with AD, LATE-NC, both, or neither. Utilizing techniques that measure the extent each cell uses or expresses specific genes, we will examine how LATE-NC and AD influence the function of brain cells. By comparing AD and LATE-NC, our findings will pave the way for developing tests to allow for more accurate diagnosis of LATE-NC while individuals are still alive.

Osama Al Dalahmah, MD, PhD (Lead/Contact PI)
Assistant Professor of Pathology and Cell Biology
oa2298@cumc.columbia.edu

Andrew Teich, MD, PhD (Co-PI)
Associate Professor of Pathology and Cell Biology (in Neurology)

Adam M. Brickman, PhD (Co-I)
Professor of Neuropsychology (in Neurology, the Taub Institute, and the Sergievsky Center)

Vilas Menon, PhD (Co-I)
Assistant Professor of Neurological Sciences (in Neurology, and the Taub Institute)

This is a new proposal to initiate studies of how alterations in neuronal nuclear architecture in patients with Alzheimer’s disease (AD) may reflect changes in nuclear mechanotransduction that in turn contribute to disease progression. Studies of mechanotransduction, the conductance of mechanical force into biological function, in neurons have lagged behind those in other more obviously mechanically engaged tissues such muscle and bone. Nonetheless, neurons possess the molecular machinery of mechanotransduction including a mechanically engaged nucleus that serves as a central integrator of mechanical force in many cell types. We have obtained preliminary data that mechanotransduction is altered in brain tissue from patients with AD and can be experimentally recapitulated in cultured rat and human neurons modeling AD in vitro. We will study neuronal mechanotransduction in AD where sequelae from genetic and molecular perturbations in AD affect neuronal architecture and mechanotransduction. Our studies may lead to both new targets to ameliorate AD pathology and broader understanding of how mechanotransduction impacts neuronal function. Our study brings together a diverse team of researchers with broad expertise in nucleocytoskeletal coupling and mechanotransduction (Gundersen), mouse models of nuclear envelopathies (Worman), pathological basis of neurological diseases (Al Dalahmah), neuronal cytoskeleton in physiology and disease (Bartolini) and human stem cell models of AD (Sproul).

Gregg G. Gundersen, PhD (Lead/Contact PI)
Professor of Pathology and Cell Biology
ggg1@cumc.columbia.edu

Osama Al Dalahmah, MD, PhD (Co-PI)
Assistant Professor of Pathology and Cell Biology

Francesca Bartolini, PhD (Co-PI)
Associate Professor of Pathology and Cell Biology

Howard J. Worman, MD (Co-PI)
Professor of Medicine and Pathology and Cell Biology

Andrew A. Sproul, PhD (Co-I)
Assistant Professor of Pathology and Cell Biology (in the Taub Institute) at the CUMC

The nematode Caenorhabditis elegans has served a remarkably successful tool to discover genes that are involved in controlling animal lifespan. Most if not all lifespan-controlling genes, identified initially in C. elegans, have similar functions in mammals, including humans, demonstrating that the molecular mechanisms of lifespan regulation are deeply conserved across the animal kingdom. In this grant proposal, we seek to elucidate the mechanisms of action of a gene that has recently been implicated in controlling animal lifespan in C. elegans. Specifically, genetic elimination of the transcription factor hlh-15 results in a substantial increase in the lifespan of C. elegans. Surprisingly, we found that hlh-15 is only expressed in a very small number of neurons in the brain of C. elegans. We propose to test in this grant proposal whether (a) those specific neurons are indeed required to control lifespan, whether (b) these neurons secrete specific neuropeptides to control lifespan and to (c) seek effector pathways of these neuropeptides. Our studies may reveal that lifespan is controlled, with remarkable cellular specificity, through a novel, central brain mechanism and may reveal novel candidate genes that control lifespan in vertebrates.

Oliver Hobert, PhD (PI) Professor of Biological Sciences and of Biochemistry and Molecular Biophysics, Biological Sciences, Columbia University
or38@columbia.edu

There is an urgent need to identify biomarkers that can help discover which individuals will eventually develop Alzheimer’ disease (AD), prior to the occurrence of significant AD pathology and irreversible neurodegeneration in the brain. In order to aid in these efforts, we are proposing the utilization of our newly developed artificial intelligence (AI)-assisted method called DeepContrast, which can detect signatures of brain activity in structural brain MRI scans. Our preliminary data has already uncovered an intriguing hippocampal hyperactivity signature in cognitively unimpaired APOE4 carriers, which may be predictive of their eventual conversion to MCI or AD. For this study, we will utilize this DeepContrast method to extract and analyze brain activity signatures from structural MRI scans that were obtained as part of the Washington Heights/Inwood Columbia Aging Project (WHICAP) study. Importantly, because of the diversity of the WHICAP cohort, we will be able to utilize these WHICAP MRI scans to investigate how the brain activity signals we observe in cognitively unimpaired APOE4 carriers differ between different race/ethnicity groups, and how these differences affect the prediction of MCI/AD conversion. We believe that the results of this study will be a major contribution to the AD field.

Tal Nuriel, PhD (Contact PI) Assistant Professor of Pathology and Cell Biology (in the Taub Institute) at the CUMC
tn2283@cumc.columbia.edu

Adam M. Brickman, PhD (Co-I)
Professor of Neuropsychology (in Neurology, the Taub Institute, and the Sergievsky Center)

Jia Guo, PhD (Co-PI)
Assistant Professor of Neurobiology (in Psychiatry) at the CUMC

Alzheimer’s disease often occurs in the setting of other brain diseases, which can also contribute to cognitive decline. How and why other brain diseases occur in the setting of Alzheimer’s disease is an outstanding question for the field. In this proposal, we investigate how the brain responds to a common co-occurring disease (Diffuse Lewy Body Disease) in the setting of Alzheimer’s disease. We use novel imaging tools in conjunction with artificial intelligence to analyze tissue slides from patients with Alzheimer’s disease, Diffuse Lewy Body Disease, and Alzheimer’s Disease with Diffuse Lewy Body Disease. We will use these tools to obtain a holistic picture of how the brain degenerates in all three conditions, what the similarities are, and how they are different. This has the potential to supply novel insights into disease mechanism and formulate testable hypotheses concerning why these two diseases co-occur in patients.

Andrew Teich, MD, PhD (PI) Associate Professor of Pathology and Cell Biology (in Neurology)
aft25@cumc.columbia.edu

Kevin L. Gardner, MD, PhD (Co-I)
Professor and Interim Chair of Pathology and Cell Biology

Hasini Reddy, MD, DPhil (Co-I)
Assistant Professor of Pathology and Cell Biology at the CUMC

Despite decades of research, no therapies exist for effective treatment of AD. To address this unmet need, a druggable therapeutic target must be identified, induced sufficiently early in the disease course to provide a suitable window for intervention to abrogate AD pathology. In AD there are increases in pathologic proteins and decreases in presumably beneficial proteins. However, there are no approved therapies that target protein decreases and dysfunctional core pathways in AD. We hypothesize that augmenting levels of critical proteins decreased in AD may provide therapeutic benefit.

The endosomal protein trafficking complex retromer and the trafficking receptor SORL1 form a functional unit dedicated to the endosomal recycling pathway. Genetics established that SORL1 deficiency can causally trigger AD. SORL1 and retromer are co-deficient in AD vulnerable brain regions. Novel macrocyclic peptides have been developed as retromer pharmacological chaperones to stabilize the retromer complex. To further develop these as therapies we used two approaches to make them cell permeant: 1) a fusion peptide of the macrocycle and the cell penetrating peptide Pen1; 2) a reducible disulfide linkage of the macrocycle with Pen1. We will compare them to determine which provides the best efficacy using non-invasive intranasal instillation in the SORL1 haplodeficient mouse model of AD.

Carol M. Troy, PhD (Contact PI) Professor of Pathology and Cell Biology and Neurology (in the Taub Institute) at the CUMC
cmt2@cumc.columbia.edu

Scott A. Small, MD (Co-PI)
Boris and Rose Katz Professor of Neurology (in the Taub Institute, the Sergievsky Center, Radiology and in Psychiatry)

Gregory A. Petsko, DPhil (Co-PI)
Professor of Neurology Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham & Women’s Hospital Harvard Medical School

With Alzheimer's Disease (AD) affecting millions globally, unraveling its genetic and molecular underpinnings is vital for developing therapies. Spatial omics profiling, a method offering insights into the molecular machenisms in relevant tissues, is at the forefront of this research. With this proposal, we seek to integrate spatial transcriptomic, epigenomic, and proteomic profiles of human brain tissue from AD cohorts, as a pilot study to our recent NIH proposal on the Alzheimer’s Disease Fuctional Genomics xQTL (FunGen-xQTL) Project. The proposed study contrasts our NIH proposal, which uses snRNA-seq on 1,000 brains from minority ancestries, by exploring the addition of other omics modalities and spatial context utilizing the latest biotechnology, as an alternative option at approximately the same cost. This study involves profiling 10 samples—5 from AD patients and 5 from healthy individuals—analyzing two brain slices each for combined ATAC-seq, gene and protein expression, on 40,000 cells per sample. By spatially aligning these modalities using gene expression as an anchor and applying our computational methods, we aim to uncover novel genetic signatures and molecular pathways relevant to AD progression. This pilot study has a high potential to significantly optimize the design of the much larger scale FunGen-xQTL project, offering insights into the functional basis of Alzheimer's and identifying new therapeutic targets.

Gao Wang, PhD (Contact PI) Assistant Professor of Neurological Sciences (in Neurology and the Sergievsky Center)
gw2411@cumc.columbia.edu

Yanxiang Deng, PhD (Co-PI)
Assistant Professor of Pathology and Laboratory Medicine, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania