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Principal Investigator: Henrieta Scholtzova
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $821,911
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Dysregulation of innate immunity is thought to be a significant contributor to Alzheimer’s disease (AD)
pathogenesis. We have focused on harnessing innate immunity via Toll-like receptor 9 (TLR9) to modulate age-
related defects in immune cells to counteract AD pathology. Our findings from multiple AD pathology transgenic
mouse models provide the first in vivo evidence that stimulation of innate immunity with TLR9 agonist CpG ODN
can reduce behavioral deficits and ameliorate all pathological hallmarks of AD. Most current immunotherapeutic
trials for AD have been associated with a major complication referred to as amyloid-related imaging abnormalities
(ARIA), which is linked to the presence and extent of cerebral amyloid angiopathy (CAA). CAA is present in a
majority of individuals with AD, and its severity is an independent risk factor for cognitive decline. Hence, it is
critical to develop a therapy effective against CAA without inducing ARIA complications. Additionally, the
premature translation of promising transgenic mice data directly to patients has been associated with a very high
clinical trial failure rate. Our recent study established that squirrel monkeys (SQMs), an NHP model that develops
extensive age-dependent CAA unlike other primates, represent an opportune environment for demonstrating the
therapeutic benefits of our immunomodulation using CpG ODN 2006. Here we propose the use of class B CpG
1018, which is currently being tested in clinical trials for a variety of indications. The collective studies are
designed to provide a comprehensive portrayal of CpG 1018 efficacy and long-term safety by integrating biofluid
biomarker signatures with imaging markers, cognitive measures, in addition to neuropathology correlates.
Disease progression and safety will also be monitored by a combination of MRI techniques, which will enable
morphometric characterization and screening for ARIA. The utility of a multi-shell diffusion MRI model to follow
CpG 1018’s treatment effects in vivo on brain microstructural integrity, especially WM integrity changes, will be
validated for the first time. An additional strength of this proposal is the use of our powerful proteomic strategy
to unveil the first comprehensive characterization of the CAA and choroid plexus (CP) proteomes in association
with disease progression and CpG 1018 intervention. This localized proteomic approach is a preferred method
as it combines unbiased mass spectrometry examination with laser capture microdissection to precisely excise
defined neuropathological lesions. A further aim of this study is to map involvement of the CP-CSF system in
immune cell trafficking in response to CpG 1018. Delineating the CAA and CP protein signatures will advance
understanding of CpG 1018’s favorable immunomodulatory capabilities, as well as provide insights into CAA
pathogenesis to improve diagnostic capability. Overall, the interventions described here will provide
essential preclinical evidence that will enhance CpG 1018’s potential for clinical application.
Terms: <2019-nCoV vaccine><AD dementia><AD model><AD pathology><Acceleration><Adjuvant><Agonist><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Amyloid><Amyloid (Aβ) plaques><Amyloid Plaques><Amyloid Substance><Assay><Autopsy><Behavioral><Bioassay><Biological Assay><Biological Markers><Biological Response Modifiers><Biomodulators><Bleeding><Blood><Blood Reticuloendothelial System><Blood Vessels><Brain><Brain Nervous System><Brain Pathology><COVID-19 vaccine><Cell Body><Cells><Cerebral Amyloid Angiopathy><Choroid Plexus><Chronic><Clinical><Clinical Trials><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complication><Congophilic Angiopathy><DWI (diffusion weighted imaging)><DWI-MRI><Data><Defect><Development><Diffusion><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease Progression><Disturbance in cognition><ELISA><Effectiveness><Elderly><Encephalon><Environment><Enzyme-Linked Immunosorbent Assay><Evaluation><FDA approved><Failure><Family><Formalin><Goals><HBV Vaccine><Hemorrhage><Hepatitis B Vaccines><Hepatitis B virus vaccine><Hortega cell><Human><Image><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunomodulation><Immunotherapeutic agent><Impaired cognition><Incidence><Individual><Inflammation><Innate Immunity><Intervention><Intervention Strategies><Label><Lesion><Link><Liquid substance><MR Imaging><MR Tomography><MRI><MRI biomarker><MRI marker><MRIs><MT-bound tau><Macrophage Activation><Magnetic Resonance Imaging><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Methods><Microglia><Modeling><Modern Man><Monitor><Monkeys><NMR Imaging><NMR Tomography><Native Immunity><Natural Immunity><Nerve Degeneration><Neuritic Plaques><Neuron Degeneration><Non-Specific Immunity><Nonspecific Immunity><Nuclear Magnetic Resonance Imaging><Paraffin Embedding><Pathogenesis><Pathologic><Pathology><Patients><Peripheral><Phenotype><Play><Primary Senile Degenerative Dementia><Primates><Primates Mammals><Process><Proteins><Proteome><Proteomics><Risk Factors><Role><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Safety><Saimiri><Saimirus><Saline><Saline Solution><Senile Plaques><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Severities><Sporadic Cerebral Amyloid Angiopathy><Squirrel Monkey><Stimulus><Structure of choroid plexus><System><TLR protein><TLR9 gene><TLR9 protein><TLR9 receptor><Techniques><Testing><Therapeutic><Time><Tissue Embedding><Toll-Like Receptor Family Gene><Toll-like receptors><Transgenic Mice><Translations><Vascular Diseases><Vascular Disorder><White Matter Hyperintensity><Zeugmatography><advanced age><age associated><age correlated><age dependent><age linked><age related><age specific><aged animal><aged animals><alzheimer model><amyloid beta plaque><amyloid pathology><amyloid-b plaque><animal old age><aβ plaques><bio-markers><biologic marker><biomarker><biomarker signature><blood loss><blood vessel disorder><brain tissue><cell type><cerebrovascular amyloidosis><clinical applicability><clinical application><clinical relevance><clinically relevant><cognitive assessment><cognitive benefits><cognitive dysfunction><cognitive loss><cognitive task><cognitive testing><cohort><cored plaque><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><dMRI><design><designing><developmental><diagnostic ability><diagnostic biomarker><diagnostic capability><diagnostic marker><diagnostic power><diagnostic utility><diagnostic value><diffuse plaque><diffused><diffuses><diffusing><diffusion tensor imaging><diffusions><elderly animal><enzyme linked immunoassay><fluid><geriatric><gitter cell><imaging><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><immune drugs><immune modulation><immune regulation><immune-based therapeutics><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunomodulatory biologics><immunoregulation><immunoregulatory><immunotherapeutics><immunotherapy agent><improved><in vivo><innovate><innovation><innovative><insight><interventional strategy><laser capture microdissection><liquid><magnetic resonance imaging biomarker><magnetic resonance imaging marker><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><mouse model><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><necropsy><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><neuropathologic><neuropathological><neuropathology><neuroprotection><neuroprotective><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-human primate><nonhuman primate><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><old animals><p-tau><p-τ><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><postmortem><posttranslational modification of tau><pre-clinical><preclinical><premature><prematurity><primary degenerative dementia><response><response to therapy><response to treatment><screening><screenings><senile dementia of the Alzheimer type><senior citizen><social group><social role><substantia alba><tau><tau Proteins><tau factor><tau phosphorylation><tau posttranslational modification><tau-1><therapeutic response><therapy response><toll-like receptor 9><trafficking><translation><treatment effect><treatment response><treatment responsiveness><vaccination study><vaccination trial><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against hepatitis B><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccine study><vaccine trial><vaccines preventing COVID><vaccines to prevent COVID><vascular><vascular dysfunction><vasculopathy><white matter><white matter change><τ Proteins><τ phosphorylation>