Around 50 million people worldwide are suffering from Alzheimer's disease (AD) and related dementias, and AD is observed primarily in aged people. Current diagnosis of AD relies primarily on observations of declines in mental and cognitive functions, when irreversible brain damage occurs. Positron emission tomography (PET) tracers for early diagnosis of AD have been developed via assessing Aß or tau levels, however aggregate-targeting tracers often suffer from high nonspecific binding. Therefore, there is an urgent need for developing novel tools targeting molecular level to improve the specificity of early diagnosis of AD. Cellular senescence has been shown to be a critical contributor disrupting the homeostasis and functions of aging brains. In aged brains, senescent cells accumulate and exert chronic inflammatory pressure on surrounding cells. Higher levels of senescence in different types of brain cells have been observed in mice and human with AD and selective removal of senescent cells reduces Aß plaque formation in mouse brain and improves cognitive functions. These findings indicate that senescence can potentially serve as an early indicator and therapeutic target for AD. However, tools for real-time in vivo senescence detection are extremely limited. Recently, the Cui group at the University of Florida (UF) has developed a series of activatable molecular probes, enabling the successful real-time imaging of senescence in animal models for the first time. These probes have high detection sensitivity produced by a self-immobilizing moiety installed on the probe so that upon activation, the probe can be covalently linked to surrounding proteins at the site of activation. Based on this strategy, SenoTrac, partnering with UF and Moffitt Cancer Center, aims to develop the first- in-class PET probes for senescence. Briefly, the novel PET probe will consist of a ß-galactoside that can be specifically cleaved by senescence-associated ß-galactosidase (SA-ß-gal), a 18F, and a self-immobilizing moiety that can anchor the probe onto surrounding proteins upon activation. We expect the activatable PET probe to have high brain uptake, minimal diffusion and high signal/background contrast with excellent spatial resolution. We will characterize these probes in vitro (SenoTrac and UF), and we will also evaluate their ability to cross the blood brain barrier in animals (UF). Radiochemistry before PET imaging will be carried at Moffitt. AD mouse model (5xFAD) will be used in the dynamic PET/CT scan to see the levels of senescence in different age groups. Additionally, we will clear senescent cells using senolytics, perform PET imaging of senescence and evaluate AD phenotypes in these mice. Ex vivo analysis of the brain tissues will provide information of other AD and senescence biomarkers (UF). We expect to draw correlation of senescence levels and various AD phenotypes. In Phase 1, we will develop the PET probes for senescence tracking in AD animal models. In Phase 2, we will evaluate the probes in different animal models, and a small-scale human trial. We will navigate the regulatory requirements, and work towards commercialization of these probes.
Public Health Relevance Statement: PROJECT NARRATIVE
Public Health Relevance Statement: Millions of people worldwide suffer from incurable Alzheimer's disease, over 95% of which is seen in people aged 65 or older, and the number continues to grow as the population ages. Senescence, a cellular state with cell cycle arrest, is tightly linked to Alzheimer's disease, and real-time detection of senescence can potentially be used as an early diagnosis for Alzheimer's disease. The proposed work will develop and evaluate positron emission tomography (PET) imaging probes for senescence detection in the brain using animal models, and eventually clinically translate them for human use in the future.
Project Terms: Age; ages; Aging; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Animals; Astrocytes; Astrocytus; Astroglia; astrocytic glia; beta-Galactosidase; beta-D-Galactosidase; beta-D-Galactoside galactohydrolase; lac Z Protein; ß-D-Galactosidase; ß-D-Galactoside galactohydrolase; ß-Galactosidase; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Brain; Brain Nervous System; Encephalon; Cell Aging; Cell Senescence; Cellular Aging; Cellular Senescence; Replicative Senescence; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Diffusion; Disease; Disorder; Animal Disease Models; Florida; Future; Galactosides; Goals; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Immobilization; orthopedic freezing; In Vitro; Molecular Probes; Mus; Mice; Mice Mammals; Murine; Persons; Glia; Glial Cells; Kolliker's reticulum; Neuroglial Cells; Non-neuronal cell; Nonneuronal cell; nerve cement; Neuroglia; Patents; Legal patent; PET; PET Scan; PET imaging; PETSCAN; PETT; Positron Emission Tomography Medical Imaging; Positron Emission Tomography Scan; Rad.-PET; positron emission tomographic (PET) imaging; positron emission tomographic imaging; positron emitting tomography; Positron-Emission Tomography; pressure; Proteins; Radiation Chemistry; Radiochemistry; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Specificity; Stress; Technology; Time; X-Ray Computed Tomography; CAT scan; CT X Ray; CT Xray; CT imaging; CT scan; Computed Tomography; Tomodensitometry; X-Ray CAT Scan; X-Ray Computerized Tomography; Xray CAT scan; Xray Computed Tomography; Xray computerized tomography; catscan; computed axial tomography; computer tomography; computerized axial tomography; computerized tomography; non-contrast CT; noncontrast CT; noncontrast computed tomography; Translating; Universities; Work; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; base; improved; Image Analysis; Image Analyses; image evaluation; image interpretation; Site; Chronic; Clinical; Diffuse; Penetration; Phase; Series; Link; Chemicals; Evaluation; screening tools; Screening procedure; uptake; non-invasive diagnosis; non-invasive diagnostic; noninvasive diagnostic; noninvasive diagnosis; Acquired brain injury; brain damage; brain-injured; Brain Injuries; Inflammatory; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; tool; cognitive function; Diagnostic Method; Diagnostic Technique; Diagnostic Procedure; brain tissue; age group; brain cell; early detection; Early Diagnosis; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; novel; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Cell Cycle Arrest; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; image-based method; imaging method; imaging modality; Detection; Disease Marker; Molecular Target; Resolution; in vivo; Cancer Center; Molecular; Tracer; Development; developmental; Image; imaging; disease phenotype; age related; age dependent; imaging probe; design; designing; Population; aged; clinically relevant; clinical relevance; Alzheimer disease detection; AD detection; Alzheimer's detection; aging brain; aged brain; Alzheimer's disease risk; Alzheimer risk factor; alzheimer risk; mouse model; murine model; therapeutic target; commercialization; aging population; aged population; population aging; senescence; senescent; public health relevance; Biological Markers; bio-markers; biologic marker; biomarker; non-invasive imaging; noninvasive imaging; mental function; risk stratification; stratify risk; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; real-time images; realtime image; Alzheimer's disease diagnosis; Alzheimer's diagnosis; Alzheimer's disease brain; Alzheimer's brain; detection sensitivity; rational design; diagnostic tool
