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Understanding the pathology of Alzheimer's disease by profiling vulnerable neurons

Understanding the pathology of Alzheimer's disease by profiling vulnerable neurons. Stephen D. Ginsberg, Ph.D. Center for Dementia Research Nathan Kline Institute Departments of Psychiatry Neuroscience & Physiology NYU Neuroscience Institute New York University Langone Medical Center.

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Understanding the pathology of Alzheimer's disease by profiling vulnerable neurons

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  1. Understanding the pathology of Alzheimer's disease by profiling vulnerable neurons Stephen D. Ginsberg, Ph.D. Center for Dementia Research Nathan Kline Institute Departments of Psychiatry Neuroscience & Physiology NYU Neuroscience Institute New York University Langone Medical Center

  2. Symptoms of dementia • Memory loss • Inability to process directions • Difficulty having a conversation • Not knowing the time or date • Inability to handle a budget • Failure to recognize family members • Change in mood and/or personality

  3. Alzheimer’s disease (AD) • Alois Alzheimer (1864-1915) • First patient Auguste D (1850-1906)

  4. AD pathology seen by Alzheimer • Alzheimer used silver stained brain sections to visualize neuropathology

  5. AD pathological hallmarks Ginsberg lab

  6. Cognitive decline across the progression of dementia

  7. Progression of dementia • Aging- normal process of senescence • Preclinical stage • Mild cognitive impairment (MCI) • Alzheimer’s disease • Down syndrome • Other neurodegenerative disorders

  8. AD gross pathology

  9. Searching for the underlying pathology of AD

  10. Laser capture microdissection (LCM)

  11. LCM of hippocampal CA1 neurons

  12. RNA-sequencing instrumentation (NYU)

  13. Clive

  14. Synapse loss is associated with cognitive decline

  15. Downregulation of synaptic markers in CA1 hippocampal neurons

  16. Dysregulated genes in CA1 neurons and regional hippocampal dissections in AD versus control subjects

  17. Mouse models

  18. Representation of classes of transcripts in wild type mice

  19. Calorie restriction reduced amyloid burden in female APP overexpressing mice

  20. Long-term CR reverses age-dependent gene changes

  21. Benefits of maternal choline supplementation (MCS) on in a model of Down syndrome (DS) and AD

  22. State of AD therapeutics • ‘Wild west’ where evidence-based results are few and far between • Current FDA approved treatments the target cholinergic system principally • Antibody therapy to remove Abeta or tau • No agents impact the progression of dementia- just provide symptomatic relief • Alternative medicine & dietary approaches

  23. Conclusions • AD is a major public health issue • Cost is prohibitive on many levels • Etiology remains unknown • Treatment options are limited • More funding and thoughtful research is required to make a societal impact Caregivers are key contributors to healthcare delivery and maintenance of dignity for patients and loved ones with dementia

  24. Acknowledgements Nathan Kline Institute & NYU Langone Medical Center Melissa J. Alldred, Ph.D. Martin J. Blaser, M.D. Moses V. Chao, Ph.D. Megan Gautier, M.S. Paul M. Mathews, Ph.D. Sang Han Lee, Ph.D. Efrat Levy, Ph.D. Ralph A. Nixon, M.D., Ph.D. Sai Charan Penikalapati, M.S. Eva Petkova, Ph.D. Arthur Saltzman, M.S. Marisa J. Schafer, M.S. Barrow Neurological Institute Elliott J. Mufson, Ph.D. Cornell University Barbara J. Strupp, Ph.D. Michigan State University Medical Center Scott E. Counts, Ph.D. Supported by the NIA, NICHD, and the Alzheimer’s Association

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