This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $426,250 to Wake Forest University Health Sciences to develop and evaluate a novel positron emission tomography (PET) radiotracer, [11C]TM-N1324, to measure levels of the G-protein coupled receptor GPR39 in rodent models and postmortem human brain tissues of Alzheimer's disease (AD). The project aims to establish the utility of this PET imaging approach for quantifying GPR39, which is implicated...
This $4.49 million project grant from the National Institutes of Health's National Institute on Aging will fund research at The Washington University to investigate the relationship between amyloid plaque deposition, cellular metabolic dysfunction, and functional brain organization in Alzheimer's disease (AD) mice models. Over three years, the researchers will use multi-photon fluorescence lifetime imaging microscopy, multi-parametric photoacoustic microscopy, and wide-field optical imaging to...
This Project Grant award of $812,030.00 from the National Institute on Aging's Aging Research Federal Grant Program (CFDA 93.866) aims to develop and optimize non-invasive imaging biomarkers to track neuroinflammation in the early stages of Alzheimer's disease (AD). The research comprises three key components: Investigating the relationship between astrocytic acetate metabolism and astrocyte reactivity in an adenovirus-induced reactive astrogliosis model, utilizing...
This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $455,009 to The General Hospital Corporation (doing business as Massachusetts General Hospital) to develop a novel [18F]-labeled amphiphilic PET probe that can cross the blood-brain barrier and track CD206+ microglia/macrophages in Alzheimer's disease. The goal is to create a non-invasive imaging method to detect anti-inflammatory M2-like microglia and macrophages, which play a key role in...
This $481,250 Project Grant was awarded by the National Institute on Aging (CFDA 93.866 Aging Research) to Vanderbilt University Medical Center (VUMC) on September 1, 2024. The award supports the development of an innovative, non-invasive MRI imaging technique to assess membrane lipid properties in Alzheimer's disease (AD). The key objectives are to: 1) verify the relationship between the MRI nuclear Overhauser enhancement (NOE) signal and lipid properties using reconstituted phospholipid...
This three-year, $3.15 million Project Grant from the National Institutes of Health's National Institute on Aging will support the development and optimization of genetically encoded fluorescent redox indicators to image oxidative stress in Alzheimer's disease mouse models. Leveraging the complementary expertise of investigators at the University of Virginia in fluorescent indicators and fluorescence imaging of redox signaling as well as metabolic drivers in Alzheimer's, the researchers will...
This federal Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) aims to develop a new blood-based biomarker for the early detection and monitoring of Alzheimer's disease (AD). The $431,826 award, made on September 15, 2024, will fund the development of monoclonal antibodies to detect a newly discovered, neurotoxic amyloid-beta (Aβ) peptide dimer that is specific to AD pathology in the brain. The project involves the University of Wollongong conducting...
The General Hospital Corporation (MGH) Research Management Division was awarded a $458,585 Project Grant from the National Institute on Aging (NIA) under the Aging Research program (CFDA 93.866) to develop a method for detecting autoantibodies against beta-amyloid in serum as a potential biomarker for Alzheimer's disease (AD). The 2-year project aims to investigate the use of small molecule compounds called CRANAD-XS to differentially tune the binding between beta-amyloid and its...
This federal Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $926,389 to Wake Forest University Health Sciences (WFUHS) to conduct a clinical PET imaging study using the radiotracer [11C]MPC-6827 to evaluate microtubule integrity as an early biomarker of Alzheimer's disease progression. The study will enroll 75 participants, including cognitively normal adults, cognitively normal adults with positive amyloid PET scans, and adults with mild...
The University of California, San Diego will receive $3,868,694 under a three-year Project Grant from the National Institute on Aging, part of the National Institutes of Health, to develop selective amyloid-responsive fluorescent probes. The goal is to uncover design principles for probes that can selectively detect aggregated forms of alpha-synuclein or tau versus amyloid-beta in solution and tissue. The university will also develop a method to characterize the distribution of amyloidogenic...
MOLECULAR CHEMILUMINESCENCE PROBES FOR IMAGING OF AMYLOID BETA IN ANIMAL MODELS - THE HIGHLY EXCITING RESULTS FROM THE RECENT CLINICAL TRIAL OF LECANEMAB FOR ALZHEIMER'S DISEASE (AD) REIGNITE TREMENDOUS ENTHUSIASM FOR AD DRUG DEVELOPMENT. LECANEMAB IS THE FIRST DRUG TO MEET ALL THE CLINICAL ENDPOINTS WITHOUT CONTROVERSY OVER THE PAST DECADES. HOWEVER, COMPARED TO OTHER DISEASES LIKE CANCER, THE PROGRESS IN AD DRUG DEVELOPMENT, BOTH IN CLINICAL AND PRECLINICAL STAGES, LAGS BEHIND. THE NUMBER OF AD THERAPEUTICS UNDER PRECLINICAL DISCOVERY IS UNQUESTIONABLY DWARFED BY THE NUMBER OF CANCER DRUGS AT SIMILAR STAGES. SEVERAL HIGH- THROUGHPUT IMAGING METHODS, SUCH AS BIOLUMINESCENCE IMAGING, HAVE SIGNIFICANTLY ACCELERATED DRUG DISCOVERY FOR CANCER RESEARCH. HOWEVER, SUCH A HIGH-THROUGHPUT IMAGING METHOD IS NOT READILY AVAILABLE FOR AD DRUG DISCOVERY. IN THIS PROPOSAL, WE PLAN TO DEVELOP "SMART" (TURN-ON) CHEMILUMINESCENCE PROBES THAT CAN ENABLE HIGH-THROUGHPUT IMAGING FOR PRECLINICAL AD RESEARCH. "SMART" (TURN-ON) FLUORESCENCE IMAGING HAS BEEN ROUTINELY USED FOR IN VITRO, CELLULAR, AND IN VIVO IMAGING. IN CONTRAST, THE EXPLORATION OF SMART CHEMILUMINESCENCE IMAGING HAS BEEN LIMITED DUE TO ITS LOW SENSITIVITY AND DEPENDENCE ON REACTIVE OXYGEN SPECIES (ROS) OR ENZYME ACTIVITY. TO ADDRESS THESE CHALLENGES, WE HAVE DEVELOPED A NOVEL CHEMILUMINESCENCE PROBE CALLED ADLUMIN-1. THROUGH EXTENSIVE VALIDATION, WE HAVE CONFIRMED THAT ADLUMIN-1 EXHIBITS TURN-ON CHEMILUMINESCENCE UPON INTERACTION WITH AMYLOID BETA (AB) SPECIES, RESULTING IN A REMARKABLE 216-FOLD INCREASE IN INTENSITY IN VITRO. NOTABLY, ADLUMIN-1 DOES NOT RELY ON ROS OR ENZYME ACTIVITY, DISTINGUISHING IT FROM OTHER CHEMILUMINESCENCE PROBES. IN VIVO TWO-PHOTON IMAGING INDICATED THAT ADLUMIN-1 WAS HIGHLY SPECIFIC FOR AB DEPOSITS. IN VIVO WHOLE-BRAIN IMAGING SHOWED THAT ADLUMIN-1 PROVIDED A 1.80-FOLD HIGHER SIGNAL FROM 5-MONTH-OLD TRANSGENIC AD (5XFAD) MICE THAN THAT FROM THE AGE-MATCHED WILD-TYPE MICE. OUR RECENT STUDY HAS FURTHER SHOWN THAT ADLUMIN-1 ENABLES HIGH-THROUGHPUT CHEMILUMINESCENCE IMAGING, AS EVIDENCED BY IMAGING 30 MICE WITHIN 30 MINUTES WITH A $100 IMAGING FEE IN A LONGITUDINAL THERAPEUTIC STUDY. ADDITIONALLY, OUR PRELIMINARY RESULTS HAVE SHOWCASED THE FEASIBILITY OF OPTICAL 3D BRAIN IMAGING USING OUR CHEMILUMINESCENCE PROBE, OPENING UP INCREDIBLE POSSIBILITIES FOR FUTURE AD RESEARCH. THIS PROPOSAL AIMS TO ADVANCE THE DEVELOPMENT OF ADLUMIN-X PROBES THROUGH IN VITRO AND IN VIVO VALIDATION, WITH THE ULTIMATE OBJECTIVE OF EMPLOYING THE MOST EFFECTIVE PROBE FOR HIGH-THROUGHPUT MONITORING OF THERAPEUTIC INTERVENTIONS IN EXPERIMENTAL AD DRUG STUDIES. OUR OVERARCHING GOAL IS TO OFFER ACCESSIBLE, HIGHLY SENSITIVE, AND COST-EFFECTIVE "PET-LIKE" OPTICAL IMAGING METHODS FOR EXPEDITING PRECLINICAL AD DRUG DEVELOPMENT.