Makoto Ishii, M.D./Ph.D.
Assistant Professor of Neuroscience and Neurology
Abigail Hiller, Research Technician
Emily Eruysal, Weill Cornell Medical Student
Zachary Myslinski, Weill Cornell Medical Student
Carrie Sha, Weill Cornell Medical Student
Sophie Pan, Weill Cornell Medical Student
Sally Wang, Neurology Resident
Past Lab Members
Laurie Pham, Research Technician
Matt McGuire, former research technician, currently University at Buffalo School of Medicine MD-PhD student
Takuya Iizumi, M.D., Ph.D., Post-doctoral Fellow
The Ishii Laboratory at Weill Cornell Medical College is interested in understanding the bidirectional relationship between brain function and systemic metabolism with an emphasis on metabolic deficits in Alzheimer’s disease and how it differs from normal aging. Our laboratory focuses on generating hypotheses derived from open questions in clinical neurology and neuroendocrinology, testing these hypotheses using molecular genetics and neuroscience techniques in the research laboratory, and whenever possible verifying these findings in human research studies.
Alzheimer’s disease is the most common cause of dementia in the elderly and remains a devastating disease with currently no cure or effective therapies. The exact pathogenesis of Alzheimer’s disease is still unclear, but a leading hypothesis is that the abnormal accumulation of amyloid-beta peptides leads to the dementia. While deficits in cognition and memory are the major clinical manifestations of Alzheimer’s disease, accelerated early body weight loss often occurs prior to the mental decline. Furthermore, weight loss is correlated with worsening disease progression and increased risk of death in Alzheimer’s disease. Therefore, brain circuits regulating body weight may be altered early in Alzheimer’s disease and could be intrinsic to the disease process. Our laboratory is interested in identifying the central and peripheral pathways regulating body weight and systemic metabolism that are altered early in Alzheimer’s disease. We approach this topic by:
Investigating how amyloid-beta disrupts brain circuits in the hypothalamus, a brain region that critically regulates body weight, and how this differs from normal aging-related weight loss
Examining how disruption of specific hypothalamic neurons by amyloid-beta and other associated factors lead to systemic metabolic deficits
Identifying alterations in key metabolic factors and signaling pathways in human study volunteers at the earliest stages of Alzheimer’s disease
To address these aims, we have adopted a “bench-to-bedside” strategy and utilize genetic, molecular, and neurophysiological approaches in mouse models, and validation in clinically relevant human studies.
Long Term Goals
By elucidating the molecular mechanisms underlying alterations in body weight/systemic metabolism in Alzheimer’s disease, we hope to advance our overall understanding of the complex interaction between body weight/systemic metabolism and brain function. The ultimate long-term goal of the laboratory is to translate these findings to the development of new diagnostic tools and novel therapeutic agents.
Dr. Ishii was interviewed by the BrightFocus Foundation about his research on understanding early weight loss in Alzheimer's disease. https://www.brightfocus.org/alzheimers/video/interview-dr-makoto-ishii
By using mouse models, we have identified that amyloid-beta can cause dysfunction in NPY-expressing neurons in the arcuate nucleus of the hypothalamus that was associated with significant body weight deficits and pathologically low leptin levels. This is the first molecular evidence for amyloid-beta mediated inhibition of hypothalamic neurons and links amyloid-beta pathology to the body weight deficits that are commonly seen in Alzheimer’s disease. http://weill.cornell.edu/news/news/2014/08/researchers-discover-link-between-alzheimers-disease-diagnosis-and-accelerated-weight-loss-dr-makoto-ishii.html
Dr. Ishii was awarded the Paul Beeson Clinical Scientist Development Award in Aging in 2015. http://weill.cornell.edu/news/awards/2016/03/dr-makoto-ishii-wins-beeson-career-development-award.html
Ishii, M., Kamel, H., and Iadecola, C. (2019). Retinol Binding Protein 4 Levels Are Not Altered in Preclinical Alzheimer's Disease and Not Associated with Cognitive Decline or Incident Dementia. Journal of Alzheimer's Disease, 67 (1): 257-263
Hiller, A. J., and Ishii, M. (2018). Disorders of Body Weight, Sleep and Circadian Rhythm as Manifestations of Hypothalamic Dysfunction in Alzheimer’s Disease. Frontiers in Cellular Neuroscience, 12:471. doi: 10.3389/fncel.2018.00471
Ishii, M. (2017). Endocrine Emergencies With Neurologic Manifestations. Continuum: Lifelong Learning in Neurology, 23 (3): 778-801
McGuire, M. J., and Ishii, M. (2016). Leptin dysfunction and Alzheimer’s disease: evidence from cellular, animal, and human studies. Cellular and Molecular Neurobiology, 36 (2): 203-217.
Ishii, M. and Iadecola, C. (2016). Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology. Biochimica et Biophysica Acta Molecular Basis of Disease, 1862 (5): 966-974.
Ishii, M.* and Iadecola, C. (2015). Metabolic and non-cognitive manifestations of Alzheimer’s disease: the hypothalamus as both culprit and target. Cell Metabolism, 22 (5): 761-776. *corresponding author
Ishii, M., Wang, G., Racchumi, G., Dyke, J. P. Iadecola, C. (2014). Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons. J. Neuroscience, 34 (27): 9096-9106.
Ishii, M., Lavi, E., Kamel, H., Gupta, A., Iadecola, C., Navi, B. B. (2014). Amyloid Beta-related Central Nervous System Angiitis Presenting with an Isolated Seizure. Neurohospitalist, 4 (2):86-89.
Ishii, M. (2014). Neurologic Complications of Non-Diabetic Endocrine Disorders. Continuum: Lifelong Learning in Neurology, 20 (3): 560-579.
Nagata-Kuroiwa, R., Furutani, N., Hara, J., Hondo, M., Ishii, M., Abe, T., Mieda, M., Tsujino, N., Motoike, T., Yanagawa, Y., Kuwaki, T., Yamamoto, M., Yanagisawa, M., Sakurai, T. (2011). Critical role of neuropeptides b/w receptor 1 signaling in social behavior and fear memory. PLoS One. Feb 24; 6 (2): e16972.
Sakakibara, I., Fujino, T., Ishii, M., Tanaka, T., Shimosawa, T., Miura, S., Zhang, W., Tokutake, Y., Yamamoto, J., Awano, M., Iwasaki, S., Motoike, T, Okamura, M., Inagaki T., Kita K., Ezaki, O., Naito, M., Kuwaki, T., Chohnan, S., Yamamoto, TT., Hammer, RE., Kodama, T., Yanagisawa, M., Sakai, J. (2009). Fasting-induced hypothermia and reduced energy production in mice lacking acetyl-CoA synthetase 2. Cell Metabolism, 9 (2):191-202.
Ishii, M., Fei, H., and Friedman, J. M (2003). Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. Proc. Natl. Acad. Sci. USA, 100: 10540-10545.
Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chimelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., Arch, J.R.S., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNutty, D.E., Liu, W., Terrett, J.A., Eishourbagy, N.A., Bergsma, D.J., and Yanagisawa, M. (1998). Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior. Cell, 92, 573-585.
Department of Neurology
Hooman Kamel (BMRI/Neurology)