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Feil Family Brain & Mind Research Institute

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Ishii Laboratory

Makoto Ishii, M.D./Ph.D.
Assistant Professor of Neuroscience and Neurology

Lab Members

Daniel Lee, 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

Past Lab Members

Abigail Hiller, former research technician, currently University of Massachusetts Medical School MD-PhD student
Laurie Pham, former 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

Our Mission

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. 

 

Figure 1: The relationship between body weight/adiposity and age-related dementia (Adapted from Ishii and Iadecola, Biochimica et Biophysica Acta Molecular Basis of Disease 2016)

 

Goals

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.

    

Figure 2: Deficits in body weight and plasma leptin levels worsen with increasing age and brain amyloid-beta brain burden in a transgenic mouse model overexpressing the amyloid precursor protein (Adapted from Ishii et al., J Neuroscience 2014)






 

Figure 3: 3 month-old transgenic mice overexpressing amyloid precursor protein (Tg2576) have significantly lower body adiposity (white hyper-intense signals on T1-weighted MRI) compared to wild-type (WT) littermates. (Adapted from Ishii et al., J Neuroscience 2014)

Figure 4: GFP labeled NPY neurons in the arcuate nuclei of the hypothalamus are evaluated by whole-cell patch clamp (with collaborator Dr. Gang Wang, BMRI).







 

Figure 5: Schematic of a proposed pathophysiological mechanism for amyloid-beta mediated inhibition of hypothalamic pathways leading to weight loss and a low leptin state. (Adapted from Ishii et al., J Neuroscience 2014)





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.

Achievements

Recent Select Publications 

  1. Ishii, M.*, Hiller, A. J., Pham, L., McGuire, M. J., Iadecola, C., and Wang, G. (2019). Amyloid-beta modulates low-threshold activated L-type calcium channels of arcuate neuropeptide Y neurons leading to calcium dysregulation and hypothalamic dysfunction. Journal of Neuroscience, Epub ahead of print; 10.1523/JNEUROSCI.0617-19.2019. *corresponding author
  2. Eruysal, E., Ravdin, L., Kamel, H., Iadecola, C., and Ishii, M.* (2019). Plasma lipocalin-2 levels in the preclinical stage of Alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 11: 646-653. *corresponding author
  3. Ishii, M. (2019). Apolipoprotein B as a New Link Between Cholesterol and Alzheimer Disease. JAMA Neurology, 76(7):751-753.
  4. 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. *corresponding author
  5. 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
  6. Ishii, M. (2017). Endocrine Emergencies With Neurologic Manifestations. Continuum: Lifelong Learning in Neurology, 23 (3): 778-801
  7. 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.
  8. 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.
  9. 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
  10. 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.
  11. 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.
  12. Ishii, M. (2014). Neurologic Complications of Non-Diabetic Endocrine Disorders. Continuum: Lifelong Learning in Neurology, 20 (3): 560-579.
  13. 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.  
  14. 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.
  15. 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.
  16. 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.

    Joint Appointments

    Department of Neurology

    Collaborators

    Costantino Iadecola

    Gang Wang

    Ping Zhou

    Josef Anrather

    Hooman Kamel (BMRI/Neurology)

    Focus Areas: 
    Neurodegeneration
    Lab Head(s): 
    Ishii, Makoto
    Lab Researchers: 
    Ishii, Makoto

    Weill Cornell Medicine Feil Family Brain & Mind Research Institute 407 E 61st St New York, NY 10065 Phone: (646) 962-8277 Fax: (646) 962-0535