Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY / ABSTRACT The main neuropathological hallmarks of Alzheimer's disease (AD) are the extracellular accumulation of amyloid plaque deposits and intracellular formation of neurofibrillary tangles (NFTs). To enable the study of disease progression and the effect of therapeutics in preclinical mouse models of AD, there is an urgent need for non- invasive methods of imaging both hallmarks in the living brain. The most established non-invasive imaging approaches at the whole animal level are magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). However, only optical techniques like near- infrared (NIR) fluorescence imaging have the theoretical spatial resolution to image individual amyloid plaques and NFTs. In contrast to PET and SPECT, NIR fluorescence has the additional advantage of using safe, non- ionizing radiation. Previous NIR fluorescence probes for AD have mostly emitted in the 600-650 nm wavelength range. While these probes can be used to provide low resolution, bulk estimates of AD pathology burden in vivo and to distinguish between AD mice and wildtype controls, they lack the ability to provide absolute quantitation and cannot be used to image non-invasively with microscopic resolution. To enable non-invasive optical imaging through the intact scalp and intact skull of mice, the wavelength of the fluorescent probe needs to be shifted into the NIR-II spectrum (1,000-1,700 nm). At these longer wavelengths, the penetration depth through tissue is increased dramatically while the background caused by intrinsic autofluorescence is minimized. Here we propose to develop and identify candidate probes for NIR-II imaging by employing two complimentary strategies. In the first approach, we will modify the chemical structure of a promising candidate probe, with existing affinity for amyloid plaques and NFTs to enhance its binding affinity and NIR-II fluorescence emission. In the second approach, we will screen an existing chemical library of > 650 NIR fluorophores using chemical structure-activity modeling and in vitro and in vivo characterization. To image our candidate NIR-II fluorophores in vivo, we will build a custom multi-modal microscope combining NIR confocal and multiphoton microscopy and fully characterize its performance with simulations and experimental validation. We will conduct longitudinal, in vivo imaging studies in AD mice to validate our developed probes and instrumentation and demonstrate for the first time non-invasive monitoring of AD pathology with microscopic resolution. The excellent scientific environment and world-class resources provided by the Massachusetts General Hospital and Harvard Medical School, as well as the internationally recognized leadership of the applicant's mentors, along with the expertise of the proposed collaborators, will be key to the successful completion of the proposed research. This K01 award will be instrumental for the applicant to strengthen his skillset with training in optical probe development and in vivo imaging in AD mice and to take the next steps towards becoming an independent researcher.
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