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Principal Investigator: Stacey J Rizzo
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $764,623
Funding agency: National Institute on Aging
Project Summary/Abstract
Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer’s disease
(AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new
therapies that are more efficacious than the four currently approved drugs for AD which provide only modest
symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which
may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and
that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the
mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively
dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this
dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease,
diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer’s disease (AD). We
hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and
AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of
the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion
to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this
proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell
types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and
mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic
insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will
investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in
progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic
AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for
AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk
factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and
healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in
normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model
of late onset AD.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><2-AG><2-arachidonoyl-glycerol><2-arachidonoyl-sn-glycerol><2-arachidonoylglycerol><2-arachidonyl-glycerol><2-arachidonylglycerol><5'-AMP-activated protein kinase><AD dementia><AD model><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><APOE e4><APOE-ε4><APOEε4><Acceleration><Age><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease risk><Alzheimers Dementia><American><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Arachidonic Acids><Astrocytes><Astrocytus><Astroglia><Autophagocytosis><Biochemical><Biologic Models><Biological Markers><Biological Models><Biology of Aging><Brain><Brain Nervous System><Cancers><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical Trials><Data><Degenerative Neurologic Disorders><Diabetes Mellitus><Diathesis><Disease><Disease Progression><Disease susceptibility><Disorder><Drugs><Encephalon><Endocannabinoids><Endogenous Cannabinoids><Enzyme Gene><Enzymes><Evaluation><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Genetic><Genetic Alteration><Genetic Change><Genetic Models><Genetic Risk><Genetic defect><Genetic predisposing factor><Glycerol Monoester Hydrolases><Glycerol-ester acylhydrolase><Goals><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Immune><Immunes><Immunomodulation><Individual><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Late Onset Alzheimer Disease><Length of Life><Lipase><Longevity><Malignant Neoplasms><Malignant Tumor><Mechanistic Target of Rapamycin><Medication><Model System><Modeling><Molecular><Monoacylglycerol Lipases><Monoglyceride Esterases><Monoglyceride Hydrolase><Monoglyceride Lipases><Mutation><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Onset of illness><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Population><Pre-Clinical Model><Preclinical Models><Prevalence><Prevention><Primary Senile Degenerative Dementia><Process><Prophylactic treatment><Prophylaxis><Public Health><RAFT1><Rapamune><Rapamycin><Regulation><Reproducibility><Research><Risk-associated variant><Role><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><Symptoms><TREM2><TREM2 gene><Testing><Therapeutic><Therapeutic Agents><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><ages><aging associated><aging related><alzheimer model><alzheimer risk><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><astrocytic glia><attenuation><autophagy><bio-markers><biologic marker><biological signal transduction><biomarker><cardiovascular disorder><cell type><co-morbid><co-morbidity><comorbidity><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diabetes><disease onset><disease prevention><disorder onset><disorder prevention><drug/agent><early onset><experiment><experimental research><experimental study><experiments><genetic approach><genetic risk factor><genetic strategy><genome mutation><health-span><healthspan><healthy aging><healthy human aging><healthy life span><high risk><hydroxymethylglutaryl-CoA-reductase kinase><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><inherited factor><inhibitor><innovate><innovation><innovative><insight><interventional strategy><late onset alzheimer><liability to disease><life span><lifespan><mTOR><mTOR Inhibitor><mTOR inhibition><malignancy><mammalian target of rapamycin><mouse model><murine model><natural aging><neoplasm/cancer><neural inflammation><neurodegenerative illness><neuroinflammation><neuroinflammatory><neuronal><neuroprotection><neuroprotective><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><normal aging><normative aging><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathway><pharmacologic><prevent><preventing><primary degenerative dementia><prophylactic><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><senile dementia of the Alzheimer type><social role><systemic inflammation><systemic inflammatory response><tool><tributyrase>