Synaptosomal Tau Project:

Project Summary

Intracellular inclusions comprised of tau proteins correlate with, and precede, cognitive deficits in multiple neurodegenerative disorders, including Alzheimer’s disease (AD). The molecular mechanisms by which intracellular tau disrupts synaptic function and impairs cognition, however, remain incompletely elucidated. To address this question, we are studying the distribution of various species of tau across neuronal synapses.

Vascular Dementia Project:

Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia

According to the World Health Organization approximately 50 million people worldwide suffer from cognitive disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is the second most common cause of cognitive abnormalities in the elderly behind Alzheimer’s disease (AD). VD has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter disease leading to dementia.

The underlying hypothesis of this proposal is that the impact of the cytotoxic environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them particularly vulnerable to the changing extracellular environment that develops with advancing age and in response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral changes.

The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality associated with dementia. We will also use a genetic approach to further examine the response of these cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities.

Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the cytotoxic CNS environment created by ageing and cerebrovascular dysfunction. A better appreciation of the contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our understanding of this growing health concern and may serve as the basis for the design of neuroprotective therapeutic strategies.

TDP-43 Encephelopathy

Investigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy

This NIH Career Development Award proposal describes a five-year career development and training plan for Dr. Margaret Flanagan, a physician-scientist in the Division of Neuropathology in the Department of Laboratory Medicine and Pathology at the University of Minnesota. Her long-term goal is to become an independent, physician-scientist leader who will make significant contributions in the field of dementia research. Her career development training plan includes the following: protected research time, focused formal graduate coursework targeted to advance her knowledge and skills in Epidemiology, a structured mentoring program with a multidisciplinary team of experienced senior scientists, and focused research experience investigating the role of neuroinflammation in Limbic predominant age-related TDP43 encephalopathy (LATE). This training plan will culminate in a successful application for independent research funding by an investigator who is prepared to take an active leadership role in transformative change leading to improved health care outcomes in dementias associated with transactive response binding protein-43 (TDP43) associated inflammation, including Alzheimer Disease (AD), hippocampal sclerosis of aging and frontotemporal dementia.

TDP43 is a highly conserved nuclear riboprotein that plays a role in a variety of cellular functions including RNA processing. More recently, it has been shown that age-related increases in dementia risk are attributed to the accumulation of multiple co-existing brain lesions, each of which contributes significantly to dementia risk. Because there are no reliable biomarkers for TDP43 or α-synuclein, it is currently impossible to accurately detect all co-existing lesions in vivo, limiting these comprehensive assessments to postmortem studies of the brain. The objective of this proposed research is to clarify the role of neuroinflammation in LATE clinical disease progression. Dr. Flanagan will investigate TDP43 associated inflammatory markers relevant to pathways of interest, co-existing neuropathologic lesions, LATE genetic risk variants and cognitive performance data in well-characterized samples from Mayo Clinic.

This work will inform on the role of TDP43-associated neuroinflammation in the development of cognitive impairment and dementia in late life and ultimately, enable the development of future preventative and therapeutic interventions. This research will provide some of the first information about neuroinflammation in LATE. In summary, a comprehensive career development plan in the context of a well-defined training, research and mentorship structure will allow Dr. Flanagan to become a successful, independent physician-scientist.

Neuropathology Core Project Summary

Autopsy remains the gold standard for the diagnosis of diseases that cause dementia. It provides knowledge essential for developing biomarkers, understanding cellular pathology responsible for the dementia, and retrospectively identifying features most reliable for early diagnosis. Without this information rational discovery of disease-modifying drugs for dementia syndromes would not be possible.

Understanding the complexity of heterogeneous and intersecting neurodegenerative disorders entails comprehensive qualitative and quantitative assessment of the central nervous system. Hence, the Neuropathology Core (NPC) is a pivotal component of the South Texas Alzheimer Center (STAC). Co-led by Margaret Flanagan, MD and Kevin Bieniek, PhD, both trained especially for establishing and leading a new Brain Bank, this core comprehensively characterizes brain and spinal cord confirming clinical diagnoses, for purposes of research, and to provide a diagnosis and advice to families. Future advancements in elucidating and intervening in the pathogenesis of Alzheimer’s disease and related dementias (ADRD) requires the study of diverse ethnoracial autopsy cohorts. The STAC NPC services a large Mexican-American Hispanic population in the South Texas region. It will generate normative (cognitively normal) and preclinical, clinical ADRD (AD, FTD/ALS, DLB, PSP, CBD, VCID) data on MA Hispanic persons. Although our current brain samples are only 15% Hispanic, our fluid biobank has over 70% Hispanics and our focused attention on recruitment should increase the proportion of Hispanic brains to over 50% over the next 5 years. A 24/7 no-cost, autopsy service, post-mortem MRI, ante-mortem imaging/clinical assessments, family interviews, medical records increase the value of tissue obtained and shared with NACC. Interpreting ethnoracial pathological heterogeneity necessitates consideration of genetic and molecular variation, hence STAC has undertaken routine WES on the 56 brains donated to date (a 400% increase since our original submission) and proposes to undertake clinical genetic testing (with genetic counseling) in families of registered donors (Clinical and Genetics/Multiomics Cores), WGS on donated brain tissue and routinely preserves frozen brain tissue for additional omic (methylation, transcriptomics, ATAC-Seq, proteomics, metabolomics) studies. The NPC employs state-of-the-art genetic and “omics” approaches to aid in the interpretation of ADRD pathologies and identification of novel disease modifiers. The NPC undertakes routine digital scanning of all slides, and spatial neuropathology. The aims of the NPC are: accessioning high-quality central nervous system autopsy biospecimens, including brain, spinal cord, skin and cerebrospinal fluid.

These goals will be achieved through the following interactive aims:

1. Conducting data driven neuropathological evaluations of this material
2. Maintaining these resources in a dynamic biorepository for use by a range of investigators
3. Leading translational neuropathology research of multi-etiology dementia, including those of degenerative, cerebrovascular, and traumatic origins
4. Educating the local scientific/trainee (REC) and lay public communities on the importance of neuropathology and neurodegeneration research
5. The Neuropathology Core will accomplish these aims through collaborative relationships with other STAC Cores and external investigators, including colleagues at other Alzheimer’s Disease Centers.