The blood-brain barrier (BBB) is one of the most complicated organs in the body and one that is difficult to adequately model in vitro. Because the BBB plays a vital role in protecting the brain from peripheral agents, it is important to understand how it functions, and how to identify when it is compromised. On the other hand, the development of CNS targeting imaging agents and drugs for neurological disorders is hindered by the great difficulty in breaching the blood-brain barrier, and it would be a major milestone to selectively manipulate the BBB to allow access of beneficial drugs, or allow egress of accumulated toxic species in the brain. Therefore, a comprehensive model of the BBB is needed, and this will depend on maintaining all of the cellular and molecular components of the BBB, which can only be accomplished in vivo. Using multiphoton microscopy and brain imaging techniques based on fluorescence, we propose to image all of the known components of the BBB to enable a better understanding of this complex organ. We will apply our tools to models of Alzheimer's disease, where a long standing controversy surrounds the role and integrity of the BBB in the disease. Finally, we will manipulate the BBB to allow imaging of candidate molecular imaging probes to quantitatively assess the localization and concentration of soluble toxic oligomers of Ab in the transgenic mouse models of Alzheimer's disease. This will resolve an important controversy concerning the role of soluble vs insoluble amyloid aggregates in the progression of the disease. Ultimately, these studies will provide insight into the overall functio of the BBB in health and disease. The overall impact of the work will be significant, as the understanding and ability to manipulate the BBB selectively will appeal to neuroscientists from a broad range of disciplines.

Public Health Relevance

This proposal aims to develop the tools to study the intact blood-brain barrier in the brain of a living mouse. Models of the blood-brain barrier in vitro cannot recapitulate the complexity of this organ, but by developing fluorescent imaging approaches in combination with intravital multiphoton microscopy we will image and interrogate this structure in its entirety. We will then address controversial hypotheses concerning the integrity of the blood-brain barrier in Alzheimer's disease and develop tools to allow molecular imaging probes to quantitatively measure diffusible aggregates of amyloid in the Alzheimer mouse brain for the first time. The results of the work will enable CNS researchers with the tools and knowledge to overcome the blood-brain barrier to allow imaging agents and drugs to reach their targets in the brain.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ETTN-A (02))
Program Officer
Conroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Pagnier, Guillaume J; Kastanenka, Ksenia V; Sohn, Miwon et al. (2018) Novel botanical drug DA-9803 prevents deficits in Alzheimer's mouse models. Alzheimers Res Ther 10:11
Funane, Tsukasa; Hou, Steven S; Zoltowska, Katarzyna Marta et al. (2018) Selective plane illumination microscopy (SPIM) with time-domain fluorescence lifetime imaging microscopy (FLIM) for volumetric measurement of cleared mouse brain samples. Rev Sci Instrum 89:053705
Wang, Xueying; Kastanenka, Ksenia V; Arbel-Ornath, Michal et al. (2018) An acute functional screen identifies an effective antibody targeting amyloid-? oligomers based on calcium imaging. Sci Rep 8:4634
Ji, Minbiao; Arbel, Michal; Zhang, Lili et al. (2018) Label-free imaging of amyloid plaques in Alzheimer's disease with stimulated Raman scattering microscopy. Sci Adv 4:eaat7715
Arbel-Ornath, Michal; Hudry, Eloise; Boivin, Josiah R et al. (2017) Soluble oligomeric amyloid-? induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol Neurodegener 12:27
Kastanenka, Ksenia V; Hou, Steven S; Shakerdge, Naomi et al. (2017) Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer's Disease. PLoS One 12:e0170275
Hou, Steven S; Bacskai, Brian J; Kumar, Anand T N (2016) Optimal estimator for tomographic fluorescence lifetime multiplexing. Opt Lett 41:1352-5
Kastanenka, Ksenia V; Bussiere, Thierry; Shakerdge, Naomi et al. (2016) Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice. J Neurosci 36:12549-12558
Bakker, Erik N T P; Bacskai, Brian J; Arbel-Ornath, Michal et al. (2016) Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases. Cell Mol Neurobiol 36:181-94
Lillis, Kyle P; Wang, Zemin; Mail, Michelle et al. (2015) Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations. J Neurosci 35:9920-34

Showing the most recent 10 out of 91 publications