SBIR-STTR Award

Given the very limited success in Alzheimer's disease (AD) drug development over the past decades an extended search for therapy beyond the amyloid-b and tau hypotheses is needed. According to one promising and underexplored hypothesis, in AD the key pathophysiological events are linked with brain insulin resistance. This hypothesis, referred to as Type 3 Diabetes (T3D), is supported by many lines of evidence including altered insulin pathways in AD brains and cognitive benefits of anti-diabetic drugs. The mechanisms of T3D pathogenesis remain unknown, however. Extensive research demonstrated that suppression of different nodes in the growth hormone (GH)/ insulin-like growth factor (IGF)/ mechanistic target of the rapamycin (mTOR) cascade slows down aging and aging-associated cognitive decline in a range of model organisms. Insulin and IGF hormonal cascades have a common ancestry and the two axes of hormonal signaling are not fully separated. Their negative feedback loops overlap, so that activation of IGF-1 receptor (IGF1R) results in suppression of insulin receptor substrate (IRS) a key node in insulin signaling. Following this evidence, we hypothesize that chronic activation of a molecular cascade downstream of IGF1 results in a negative feedback suppression of insulin signaling (Fig. 1) in the brain and T3D development. Additionally, IGF1R negatively regulates autophagy and positively regulates NF-kB-mediated inflammation providing bridges between T3D, misfolded proteins, and inflammatory mechanisms of AD and AD-related dementias (ADRD). Informed by this hypothesis, we have conducted preliminary proof of a principle longevity experiments with mice in which small molecule IGF1R inhibitors orally administered starting 13 months of age (~45 human years) prevented the decline of short-term memory, prevented the development of insulin resistance, improved grip strength, decreased frailty, and increased lifespan. Capitalizing on these results the current proposal will allow us to make further steps toward the development of AD therapy based on IGF1R inhibition via the following aims: (1) to optimize drug-candidate molecules via computational modeling and subsequent testing of their target affinity and selectivity, toxicity properties, absorption, distribution, metabolism, and excretion characteristics; and (2) to characterize neurodegeneration prevention by optimized molecules using two mouse models: wildtype mice naturally developing cognitive decline with age and 3xTg-AD mouse model of AD. The ability of optimized drugs to improve cognitive function and improve markers of insulin signaling, autophagy, inflammation, Aß, and tau pathology in their brains will be analyzed. This project will result in a candidate drug(s) for AD and ADRD, targeting novel molecular mechanisms and ready for preclinical development.

Public Health Relevance Statement:
This project is focusing on the development of novel drug therapy for the prevention and treatment of Alzheimer's Disease (AD) and AD-related dementias. The new therapy will target brain insulin resistance - a putative mechanism of AD known as Type 3 Diabetes. In the course of the project, new drugs will be optimized and tested for therapeutic effects associated with AD and AD-related dementias. Terms:

Given the very limited success in Alzheimer's disease (AD) drug development over the past decades an extended search for therapy beyond the amyloid-b and tau hypotheses is needed. According to one promising and underexplored hypothesis, in AD the key pathophysiological events are linked with brain insulin resistance. This hypothesis, referred to as Type 3 Diabetes (T3D), is supported by many lines of evidence including altered insulin pathways in AD brains and cognitive benefits of anti-diabetic drugs. The mechanisms of T3D pathogenesis remain unknown, however. Extensive research demonstrated that suppression of different nodes in the growth hormone (GH)/ insulin-like growth factor (IGF)/ mechanistic target of the rapamycin (mTOR) cascade slows down aging and aging-associated cognitive decline in a range of model organisms. Insulin and IGF hormonal cascades have a common ancestry and the two axes of hormonal signaling are not fully separated. Their negative feedback loops overlap, so that activation of IGF-1 receptor (IGF1R) results in suppression of insulin receptor substrate (IRS) a key node in insulin signaling. Following this evidence, we hypothesize that chronic activation of a molecular cascade downstream of IGF1 results in a negative feedback suppression of insulin signaling (Fig. 1) in the brain and T3D development. Additionally, IGF1R negatively regulates autophagy and positively regulates NF-kB-mediated inflammation providing bridges between T3D, misfolded proteins, and inflammatory mechanisms of AD and AD-related dementias (ADRD). Informed by this hypothesis, we have conducted preliminary proof of a principle longevity experiments with mice in which small molecule IGF1R inhibitors orally administered starting 13 months of age (~45 human years) prevented the decline of short-term memory, prevented the development of insulin resistance, improved grip strength, decreased frailty, and increased lifespan. Capitalizing on these results the current proposal will allow us to make further steps toward the development of AD therapy based on IGF1R inhibition via the following aims: (1) to optimize drug-candidate molecules via computational modeling and subsequent testing of their target affinity and selectivity, toxicity properties, absorption, distribution, metabolism, and excretion characteristics; and (2) to characterize neurodegeneration prevention by optimized molecules using two mouse models: wildtype mice naturally developing cognitive decline with age and 3xTg-AD mouse model of AD. The ability of optimized drugs to improve cognitive function and improve markers of insulin signaling, autophagy, inflammation, Aß, and tau pathology in their brains will be analyzed. This project will result in a candidate drug(s) for AD and ADRD, targeting novel molecular mechanisms and ready for preclinical development.

Public Health Relevance Statement:
This project is focusing on the development of novel drug therapy for the prevention and treatment of Alzheimer's Disease (AD) and AD-related dementias. The new therapy will target brain insulin resistance - a putative mechanism of AD known as Type 3 Diabetes. In the course of the project, new drugs will be optimized and tested for therapeutic effects associated with AD and AD-related dementias. Terms: <3xTg; 3xTg-AD mice; 3xTg-AD mouse; a beta peptide; aberrant folded protein; aberrant folded proteins; abeta; abnormal folded protein; abnormal folded proteins; absorption; AD dementia; AD model; AD related dementia; ADRD; advanced age; Affect; Affinity; age associated decline; age associated neurodegeneration; age associated neurodegenerative disease; age associated neurodegenerative disorder; age dependent decline; age dependent neurodegeneration; age dependent neurodegenerative condition; age dependent neurodegenerative disease; age dependent neurodegenerative disorder; Age Months; age related decline; age related neurodegeneration; age-driven neurodegenerative disorders; age-related neurodegenerative disease; age-related neurodegenerative disorder; aged; aged mice; aged mouse; Aging; aging associated; aging associated neurodegeneration; aging associated neurodegenerative disease; aging related; aging related neurodegeneration; aging related neurodegenerative disease; aging related neurodegenerative disorder; Alzheimer beta-Protein; Alzheimer disease dementia; alzheimer model; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer Type Dementia; Alzheimer's; Alzheimer's amyloid; Alzheimer's Amyloid beta-Protein; Alzheimer's and related dementias; Alzheimer's brain; Alzheimer's Disease; Alzheimer's disease and related dementia; Alzheimer's disease and related disorders; Alzheimer's disease brain; Alzheimer's disease model; Alzheimer's disease or a related dementia; Alzheimer's disease or a related disorder; Alzheimer's disease or related dementia; Alzheimer's disease related dementia; Alzheimer's disease therapy; Alzheimer's therapy; Alzheimers Dementia; Amyloid Alzheimer's Dementia Amyloid Protein; amyloid beta; Amyloid Beta-Peptide; Amyloid beta-Protein; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; amyloid-b protein; anti-diabetic; Anti-diabetic Agents; Anti-diabetic Drugs; Autophagocytosis; autophagy; Aß; beta amyloid fibril; biological signal transduction; Brain; Brain Nervous System; Cell Communication and Signaling; Cell Signaling; Characteristics; chemical property; Chronic; Clinical; cognitive benefits; Cognitive decline; Cognitive Disturbance; cognitive dysfunction; cognitive function; Cognitive function abnormal; Cognitive Impairment; cognitive loss; Complex; computational modeling; computational models; computer based models; Computer Models; computerized modeling; Computerized Models; decline with age; Development; developmental; diabetes; Diabetes Mellitus; diabetes pathogenesis; Dimethylbiguanidine; Dimethylguanylguanidine; Disease; Disease Progression; Disorder; Disturbance in cognition; drug candidate; drug development; Drug Kinetics; drug/agent; Drugs; Elderly; elderly mice; elongating the lifespan; Encephalon; Event; excretion; Excretory function; experiment; experimental research; experimental study; experiments; extend life span; extend lifespan; Feedback; FK506 Binding Protein 12-Rapamycin Associated Protein 1; FKBP12 Rapamycin Complex Associated Protein 1; frailty; FRAP1; FRAP1 gene; FRAP2; geriatric; glucose metabolism; Goals; Grip strength; Growth Hormone; Growth Hormone 1; growth hormone deficiency; Growth Hormone Receptor; Hand Strength; Hep G2; HepG2; HepG2 cell line; Hormonal; hormonal signals; hormone signals; Human; Humulin R; IGF Type 1 Receptor; IGF-1 Receptor; IGF-I Receptor; IGF1; IGF1 gene; IGFI; Immediate Memory; Immunoglobulin Enhancer-Binding Protein; Impaired cognition; improved; In Vitro; in vivo; Increase lifespan; Inflammation; Inflammatory; Inflammatory Response; inhibitor; Insulin; Insulin Receptor; Insulin Receptor Protein-Tyrosine Kinase; Insulin Receptor Substrate 1; insulin receptor substrate 1 protein; Insulin Resistance; insulin resistant; insulin signaling; Insulin Signaling Pathway; insulin tolerance; Insulin-Dependent Tyrosine Protein Kinase; Insulin-Like Growth Factor 1 Receptor; Insulin-Like Growth Factor Type 1 Receptor; Insulin-Like Growth Factors; Insulin-Like-Growth Factor I Receptor; insulinlike growth factor; Intermediary Metabolism; Intervention; Intervention Strategies; interventional strategy; Intracellular Communication and Signaling; intraoral drug delivery; IRS-1 protein; kappa B Enhancer Binding Protein; Kinases; Knock-out Mice; Knockout Mice; KO mice; Length of Life; lifespan extension; Link; long-term memory; Longevity; Maintenance; mammalian target of rapamycin; Mechanistic Target of Rapamycin; Mediating; Medication; MEKs; Metabolic Processes; Metabolism; Metformin; Mice; Mice Mammals; microtubule bound tau; microtubule-bound tau; misfolded protein; misfolded proteins; model organism; Modeling; Modern Man; Molecular; Motor; mouse model; MT-bound tau; mTOR; Murine; murine model; Mus; N,N-dimethyl-imidodicarbonimidic diamide; Nerve Degeneration; neural degeneration; neural inflammation; neurodegeneration; neurodegenerative; neuroinflammation; neuroinflammatory; neurological degeneration; Neuron Degeneration; neuronal degeneration; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; NF-kappa B; NF-kappaB; NF-kB; NFKB; novel; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapeutics; novel therapy; Novolin R; Nuclear Factor kappa B; nuclear factor kappa beta; Nuclear Transcription Factor NF-kB; Null Mouse; old mice; Oral Administration; Oral Drug Administration; Pathologic; Pathology; pathway; Pathway interactions; Pharmaceutical Preparations; Pharmacokinetics; Phosphorylation; Phosphotransferase Gene; Phosphotransferases; Pituitary Growth Hormone; pre-clinical development; preclinical development; prevent; preventing; Prevention; Prevention therapy; primary degenerative dementia; Primary Senile Degenerative Dementia; Property; prophylactic; Protein Phosphorylation; proteotoxic protein; proteotoxin; RAFT1; receptor; Receptor Inhibition; Receptor Protein; Regular Insulin; Research; senile dementia of the Alzheimer type; senior citizen; Short-Term Memory; Signal Transduction; Signal Transduction Systems; Signaling; small molecular inhibitor; small molecule; small molecule inhibitor; soluble amyloid precursor protein; Somatomedins; somatotropic hormone; Somatotropin; Somatotropin Receptor; Somatotropin Receptors; success; Sulfation Factor; tau; tau factor; tau Proteins; Testing; Therapeutic; Therapeutic Effect; therapeutic evaluation; therapeutic testing; Toxic effect; Toxicities; Transcription Factor NF-kB; Transphosphorylases; Wild Type Mouse; wildtype mouse; working memory; τ Proteins