SBIR-STTR Award

(FAST-TRACK APPLICATION) Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 5.4 million individuals in the United States alone. The complexity and multifactorial nature of AD pose unique challenges for the development of effective therapies. Efforts to target specific AD-related pathways have shown promise in animal studies, only to fail during human trials. There is a pressing need to identify novel therapeutic targets and develop new drug candidates for AD. Carriers of apolipoprotein (apo) E4, one of the three apoE isoforms (apoE2, apoE3, apoE4), are associated with 60–80% of all AD cases, making apoE4 the major genetic risk factor for AD. This proposal builds on four novel findings from our studies of mouse models and human induced pluripotent stem cell (hiPSC)–derived neurons expressing different apoE isoforms. First, expression of apoE4 in knock-in (KI) mice causes age- dependent and cell-autonomous impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with hippocampal network activity deficits and learning and memory impairments. Second, optogenetic inhibition of hilar GABAergic interneuron activity impairs spatial learning and memory in wildtype mice, indicating that hilar GABAergic interneuron impairment can directly cause cognitive deficits. Third, treatment with the GABAA receptor potentiator pentobarbital or transplantation of mouse inhibitory neuron progenitors into the hippocampal hilus rescues the learning and memory deficits in apoE4-KI mice. Fourth, apoE4 expression results in GABAergic interneuron death in hiPSC-derived neuronal cultures and in the hippocampal hilus in AD patients. Together, these findings strongly suggest that apoE4 causes GABAergic interneuron impairment, leading to learning and memory deficits, and represents a novel therapeutic target for AD. We recently identified two classes of small molecules capable of protecting GABAergic neurons from apoE4’s detrimental effects. This proposal aims to further develop, optimize, and validate compounds targeting apoE4-induced GABAergic interneuron impairment as a novel therapeutic approach for AD. The goals of this proposal are 1) to perform ADME and physicochemical studies of the initial compounds and establish a pharmacodynamic (PD) marker by in vivo hippocampal electrophysiological recordings in apoE4-KI mice, 2) to identify and optimize the lead small-molecule GABAergic interneuron protectors through structure-activity relationship studies as well as pharmacokinetic and PD studies, and 3) to test the efficacy of the lead small- molecule GABAergic interneuron protectors in apoE4-KI mice and hiPSC-derived neurons carrying the apoE4 allele.

Public Health Relevance Statement:
PROJECT NARRATIVE The goals of this proposal are to develop and optimize compounds targeting apolipoprotein (apo) E4–induced GABAergic interneuron impairment as a novel therapeutic approach for Alzheimer’s disease and to test the efficacy of the lead GABAergic interneuron protectors in apoE4-knock-in mice and human induced pluripotent stem cell–derived neurons carrying the apoE4 allele. !

NIH Spending Category:
Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Dementia; Genetics; Neurodegenerative; Neurosciences; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human

Project Terms:
Affect; Age of Onset; age related; Alleles; Alzheimer's Disease; Alzheimer's disease risk; Animals; Apolipoprotein E; apolipoprotein E-3; apolipoprotein E-4; Cells; Cessation of life; Clinical Research; Cognitive deficits; Development; Dose; drug candidate; Drug Kinetics; effective therapy; efficacy testing; Electrophysiology (science); Functional disorder; Genes; genetic risk factor; Goals; Hilar; Hippocampus (Brain); Human; Impaired cognition; Impairment; in vivo; Individual; induced pluripotent stem cell; inhibitory neuron; Interneurons; Knock-in; Knock-in Mouse; Lead; lead optimization; Learning; Memory; Memory impairment; mouse model; Mus; Nature; nerve stem cell; Neurodegenerative Disorders; Neurons; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; optogenetics; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pentobarbital; pharmacodynamic biomarker; Pharmacodynamics; pharmacokinetics and pharmacodynamics; prevent; Protein Isoforms; receptor; Risk; Small Business Innovation Research Grant; small molecule; Structure-Activity Relationship; System; Transplantation; United States

(FAST-TRACK APPLICATION) Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 5.4 million individuals in the United States alone. The complexity and multifactorial nature of AD pose unique challenges for the development of effective therapies. Efforts to target specific AD-related pathways have shown promise in animal studies, only to fail during human trials. There is a pressing need to identify novel therapeutic targets and develop new drug candidates for AD. Carriers of apolipoprotein (apo) E4, one of the three apoE isoforms (apoE2, apoE3, apoE4), are associated with 60–80% of all AD cases, making apoE4 the major genetic risk factor for AD. This proposal builds on four novel findings from our studies of mouse models and human induced pluripotent stem cell (hiPSC)–derived neurons expressing different apoE isoforms. First, expression of apoE4 in knock-in (KI) mice causes age- dependent and cell-autonomous impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with hippocampal network activity deficits and learning and memory impairments. Second, optogenetic inhibition of hilar GABAergic interneuron activity impairs spatial learning and memory in wildtype mice, indicating that hilar GABAergic interneuron impairment can directly cause cognitive deficits. Third, treatment with the GABAA receptor potentiator pentobarbital or transplantation of mouse inhibitory neuron progenitors into the hippocampal hilus rescues the learning and memory deficits in apoE4-KI mice. Fourth, apoE4 expression results in GABAergic interneuron death in hiPSC-derived neuronal cultures and in the hippocampal hilus in AD patients. Together, these findings strongly suggest that apoE4 causes GABAergic interneuron impairment, leading to learning and memory deficits, and represents a novel therapeutic target for AD. We recently identified two classes of small molecules capable of protecting GABAergic neurons from apoE4’s detrimental effects. This proposal aims to further develop, optimize, and validate compounds targeting apoE4-induced GABAergic interneuron impairment as a novel therapeutic approach for AD. The goals of this proposal are 1) to perform ADME and physicochemical studies of the initial compounds and establish a pharmacodynamic (PD) marker by in vivo hippocampal electrophysiological recordings in apoE4-KI mice, 2) to identify and optimize the lead small-molecule GABAergic interneuron protectors through structure-activity relationship studies as well as pharmacokinetic and PD studies, and 3) to test the efficacy of the lead small- molecule GABAergic interneuron protectors in apoE4-KI mice and hiPSC-derived neurons carrying the apoE4 allele.

Public Health Relevance Statement:
PROJECT NARRATIVE The goals of this proposal are to develop and optimize compounds targeting apolipoprotein (apo) E4–induced GABAergic interneuron impairment as a novel therapeutic approach for Alzheimer’s disease and to test the efficacy of the lead GABAergic interneuron protectors in apoE4-knock-in mice and human induced pluripotent stem cell–derived neurons carrying the apoE4 allele.

Project Terms:
Affect; Age of Onset; age related; Alleles; Alzheimer's Disease; Alzheimer's disease risk; Animals; Apolipoprotein E; apolipoprotein E-3; apolipoprotein E-4; Cells; Cessation of life; Clinical Research; Cognitive deficits; Development; Dose; drug candidate; Drug Kinetics; effective therapy; efficacy testing; Electrophysiology (science); Functional disorder; Genes; genetic risk factor; Goals; Hilar; Hippocampus (Brain); Human; Impaired cognition; Impairment; in vivo; Individual; induced pluripotent stem cell; inhibitory neuron; Interneurons; Knock-in; Knock-in Mouse; Lead; lead optimization; Learning; Memory; Memory impairment; mouse model; Mus; Nature; nerve stem cell; Neurodegenerative Disorders; Neurons; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; optogenetics; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pentobarbital; pharmacodynamic biomarker; Pharmacodynamics; pharmacokinetics and pharmacodynamics; prevent; Protein Isoforms; receptor; Risk; Small Business Innovation Research Grant; small molecule; Structure-Activity Relationship; System; Transplantation; United States; Wild Type Mouse