Phase I Amount
$1,354,952
Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by progressively worsening dementia. AD currently affects over 6.2 million persons in the U.S. and approximately 30 million world-wide with 70% over the age of 65. The total public health cost of AD is expected to reach over $20 trillion by 2050. Despite extensive efforts to develop AD therapies including small molecules, monoclonal antibodies and peptide-based drugs, only aducanumab, whose efficacy is in doubt, has been approved by the FDA since 2004. A major challenge is elucidating the molecular pathology involved in AD in order to develop effective early diagnostics and drugs. While amyloid plaque formation due to aggregation of different Aß-peptides has been an important focus, a myriad of other molecules including tau, neuronal and glial receptors, endosomal-lysosomal related proteins, glycans, phospholipids, cholesterol and metabolites have also been implicated in AD pathology. In order to obtain a detailed understanding of the possible role of these diverse molecular species as well as the molecular targeting of candidate drugs, there is an urgent need to develop sufficiently powerful, highly multiplexed and multiomic tissue imaging techniques that can map at cellular resolution the 2D-spatial distribution and association of these diverse, AD molecular players. The proposed Phase II project seeks to address this challenge by applying a new highly- multiplexed, targeted method termed mass spectrometric imaging immunohistochemistry (MSI-IHC). MSI- IHC is based on the use of novel photocleavable mass-tags (PC-MTs) developed by AmberGen which when linked to antibody or lectin probes enable targeted biomolecules to be identified in the mass spectrometric image. This approach significantly exceeds the multiplex capability of fluorescence immunohistochemistry (IHC) and previous cleavable mass-tag based methods which are generally limited to 5 biomarkers or require extensive cycling procedures in the case of fluorescence. In addition, the ability to combine MSI-IHC with label-free, untargeted small molecule mass spectrometric imaging (MSI) as well as fluorescence IHC imaging, on the same sample, greatly extends its power. This is possible using unique double-labeled fluorescent-PC-MT probes and performing 2 rounds of MSI. Together, these innovations can provide a much more comprehensive multiomic picture of the role of various molecules in AD pathology. In Phase I, we have demonstrated the feasibility of this approach on mouse and human brain tissue specimens including the ability to image simultaneously a variety of AD related molecules. In Phase II we will build on this progress by applying MSI-IHC to human and transgenic AD mouse brain tissue obtained from collaborators and commercial sources. One goal, in collaboration with Prof. R.A. Nixon at NYU, a leading AD researcher, will be to investigate the role of neuronal endosomal dysfunction, the earliest known pathobiology specific to AD. Image analysis with be performed using novel statistical physics and AI methods previously developed for AD tissue and brain imaging.
Public Health Relevance Statement: Narrative Alzheimer's Disease (AD) kills more people in the U.S. every year than breast and prostate cancers combined. A major challenge is elucidating the molecular processes involved in AD pathology and to develop drugs that can delay or block these processes. The Phase II project will evaluate a new spatial multiomics approach developed by AmberGen based on novel photocleavable mass-tags and mass spectrometric imaging. This approach enables the multiomic mapping at cellular resolution of AD brain tissue to reveal the spatial distribution and association of hundreds of key molecules suspected to play a role in AD pathology including polypeptides, proteins, lipids, glycans and metabolites as well as AD targeted drug candidates.
Project Terms: Resolution; Validation; Molecular; Process; molecular imaging; molecule imaging; Image; imaging; design; designing; AD transgenic mice; Alzheimer's disease transgenic mice; Alzheimer's transgenic mice; Imaging technology; innovation; innovate; innovative; human disease; mouse model; murine model; commercialization; FDA approved; Biological Markers; bio-markers; biologic marker; biomarker; drug candidate; operation; Drug Targeting; Big Data; BigData; Alzheimer's disease pathology; AD pathology; Alzheimer's pathology; multiple omics; multiomics; peptide drug; Peptide-based drug; therapeutic peptide; Tissue imaging; Molecular Disease; Multiomic Data; multiple omic data; Aducanumab; BIIB037; aduhelm; Alzheimer's disease therapy; Alzheimer's therapy; Alzheimer's disease brain; Alzheimer's brain; mass spectrometric imaging; imaging mass spectrometry; Affect; Agar; 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; Antibodies; Monoclonal Antibodies; Clinical Treatment Moab; mAbs; Autopsy; necropsy; postmortem; Biotechnology; Biotech; Boston; Brain Diseases; Brain Disorders; Encephalon Diseases; Intracranial CNS Disorders; Intracranial Central Nervous System Disorders; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Cholesterol; Data Analyses; Data Analysis; data interpretation; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Fluorescence; Goals; Hospitals; Human; Modern Man; Immunohistochemistry; Immunohistochemistry Cell/Tissue; Immunohistochemistry Staining Method; Institutes; Lectin; Lipids; Maps; Methods; Transgenic Mice; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Persons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Peptides; Phosphatides; Phospholipids; Physics; Play; Glycans; Polysaccharides; Production; Proteins; Public Health; Research; Investigators; Researchers; Research Personnel; social role; Role; Spatial Distribution; Tissues; Body Tissues; Universities; Woman; 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; Imaging Techniques; Imaging Procedures; Imaging Technics; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Health Care Costs; Health Costs; Healthcare Costs; Uncertainty; doubt; base; Label; Procedures; Image Analysis; Image Analyses; image evaluation; image interpretation; Brain imaging; brain visualization; Chronic; Phase; Link; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Collaborations; Letters; MALD-MS; MALDI; MALDI-MS; Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization; matrix assisted laser desorption ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; PSEN1; S182 protein; presenilin 1 protein; presenilin-1; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; instrument; Diagnostic; Research Specimen; Specimen; machine learned; Machine Learning; Malignant Tumor of the Prostate; Malignant prostatic tumor; Prostate CA; Prostate Cancer; Prostatic Cancer; Malignant neoplasm of prostate; Source; brain tissue; Amentia; Dementia; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; 65+ years old; Aged 65 and Over; age 65 and greater; age 65 and older; aged 65 and greater; aged â¥65; old age; human old age (65+); molecular pathology; Receptor Protein; receptor; cohort; novel; Modeling; Sampling; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; polypeptide; small molecule; Address; Molecular Target
