Understanding the pathology of Alzheimers disease by profiling

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

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

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

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

AD pathological hallmarks Ginsberg lab

Cognitive decline across the progression of dementia

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

AD gross pathology

Searching for the underlying pathology of AD

Laser capture microdissection (LCM)

LCM of hippocampal CA 1 neurons

RNA-sequencing instrumentation (NYU)

Clive

Synapse loss is associated with cognitive decline

Downregulation of synaptic markers in CA 1 hippocampal neurons

Dysregulated genes in CA 1 neurons and regional hippocampal dissections in AD versus control subjects

Mouse models

Representation of classes of transcripts in wild type mice

Calorie restriction reduced amyloid burden in female APP overexpressing mice

Long-term CR reverses age-dependent gene changes

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

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

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

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