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Principal Investigator: Varghese John
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $639,946
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Our recent discovery of orally brain permeable small molecules that mimic the bioactivity of Humanin (HN)
peptide to enhance and normalize neuronal phospho-Akt (p-Akt) levels provides a unique opportunity for
evaluating this new approach in Alzheimer's disease (AD). In this proposal, we will direct our efforts to
optimize this new class of agents, focusing on screening additional hits, enhancing their potency, drug-like
properties, solubility, oral brain permeability and efficacy in an AD model towards development of this novel
therapeutic approach for AD. We will also use modeling to identify HN based peptidomimetics for testing. Our
data show that these small molecule HN mimetics, like HN, can suppress neuronal death through its activation
of the gp130 receptor and signaling via the PI3/Akt pathway and provide neuroprotection for primary
hippocampal neurons against N-methyl D-aspartate (NMDA) and Aβ-induced neurotoxicity. HN is a naturally
occurring mitochondrial-derived brain peptide that decreases with age and may act as a neuroprotective factor
against AD-relevant neurotoxicity. Treatment of hippocampal neurons with our HN mimetic compound 2
resulted in an increase in p-Akt, and this correlated to its observed neuroprotective effects. In AD patients, a
significant decrease in p-Akt has been reported. Similarly, in aged apolipoprotein E4 (ApoE4) mice, there is a
significant decrease in p-Akt in the brain relative to age-matched ApoE3 mice suggesting that PI3/Akt signaling
is affected by ApoE4, a risk factor in AD. Activation of PI3/Akt signaling can transcriptionally modulate genes
related to memory such as choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT)
and may also regulate postsynaptic proteins involved in neuroplasticity. AD is the most prevalent age-related
dementia, currently afflicting more than 5.4 million people in the US. Given the urgent need for new
therapeutic approaches for AD, these HN mimetics could provide promising lead candidates for therapeutic
development. In Aim 1, we plan to evaluate small molecule HN mimetics and peptidomimetics for activation of
gp130 and normalization of p-Akt along with their neuroprotection against Aβ and NMDA induced neurotoxicity.
In Aim 2, we would conduct a design and synthesis campaign using current SAR and new docking/modeling
data to identify small mimetics, peptides and peptidomimetics. We will optimize potency, drug-like properties,
solubility and oral brain bioavailability for efficacy testing. The best analogs/peptidomimetics from Aims 1 and 2
will undergo in vitro ADMET profiling and pharmacokinetic (PK) studies, along with phosphoproteomics
analyses, in Aim 3 to prioritize the optimal compounds for in vivo efficacy testing in the ApoE4(TR):5XFAD
murine model of AD as part of Aim 4. The goal is to identify orally available HN-mimetics that
enhance/normalize brain p-Akt levels and improve cognition. Like HN itself, they could also have broader
therapeutic applications in traumatic brain injury (TBI), stroke, Aβ-induced cerebrovascular dementia,
amyotrophic lateral sclerosis (ALS) and could lead to a new class of preclinical candidates for AD.
Terms: <AD dementia><AD model><APOE e4><APOE-ε4><APOEε4><Affect><Age><Agonist><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's disease therapeutic><Alzheimer's patient><Alzheimer's therapeutic><Alzheimers Dementia><Amentia><Amino Acids><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Apoplexy><Artificial Membranes><Assay><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Aβ><Binding><Binding Proteins><Bioassay><Bioavailability><Biological><Biological Assay><Biological Availability><Body Tissues><Brain><Brain Nervous System><Brain Trauma><Brain Vascular><Brain Vascular Accident><CNS plasticity><CNTF Receptor><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Membrane Permeability><Cell Signaling><Cell surface><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemistry><Choline Acetylase><Choline Acetyltransferase><Choline O-Acetyltransferase><Chondrocytes><Ciliary Neurotrophic Factor Receptor><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Cornu Ammonis><Critical Paths><Critical Pathways><Data><Dementia><Development><Diabetes Mellitus><Disease><Disorder><Disturbance in cognition><Docking><Dose><Drug Kinetics><Drugs><ESI gene><ESI protein><Elastase-Specific Inhibitor><Encephalon><Evaluation><Exposure to><External Domain><Extracellular Domain><GP130><Gehrig's Disease><Gene Transcription><Genes><Genetic Transcription><Goals><High Throughput Assay><Hippocampus><Human><IL6ST><IL6ST gene><Impaired cognition><In Vitro><Interleukin 6 Signal Transducer><Intracellular Communication and Signaling><Isoforms><Lead><Learning><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><Lou Gehrig Disease><MK 801><MK801><Medication><Medicinal Chemistry><Membrane><Memory><Mice><Mice Mammals><Microsomes><Mitochondria><Modeling><Modern Man><Molecular Interaction><Murine><Mus><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-Aspartate Receptors><N-Methyl-D-aspartate><N-Methylaspartate><N-Methylaspartate Receptors><NMDA><NMDA Receptor-Ionophore Complex><NMDA Receptors><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neuronal Plasticity><Neurons><Oral><PI3><PI3 gene><Pathway interactions><Patients><Pb element><Penetrance><Peptides><Permeability><Persons><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Physiologic Availability><Population><Primary Senile Degenerative Dementia><Property><Protein Binding><Protein Isoforms><Proteinase Inhibitor 3><Proteins><Proteomics><RNA Expression><Receptor Protein><Reporting><Risk Factors><SKALP><Safety><Series><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solubility><Stroke><Study models><TRAPPIN 2><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Transcription><Traumatic Brain Injury><VAChT protein><a beta peptide><abeta><acetylcholine transporter><age associated><age correlated><age dependent><age linked><age related><age specific><aged><ages><alzheimer model><aminoacid><amyloid beta><amyloid-b protein><analog><antagonism><antagonist><apo E-3><apo E-4><apo E3><apo E4><apo epsilon4><apoE epsilon 4><apoE-3><apoE-4><apoE3><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-3><apolipoprotein E-4><apolipoprotein E3><apolipoprotein E4><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><beta amyloid fibril><biologic><biological signal transduction><bound protein><brain attack><brain tissue><central nervous system plasticity><cerebral vascular><cerebral vascular accident><cerebro-vascular><cerebrovascular><cerebrovascular accident><cognitive dysfunction><cognitive loss><data modeling><design><designing><determine efficacy><developmental><diabetes><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><elafin><evaluate efficacy><examine efficacy><gp130 Transducer Chain><heavy metal Pb><heavy metal lead><high throughput screening><hippocampal><humanin><improved><in silico><in vivo><lead candidate><lead optimization><membrane permeability><membrane structure><meter><mimetics><mitochondrial><model of data><model the data><modeling of the data><mouse model><murine model><nerve cell death><nerve cell loss><neural degeneration><neural plasticity><neurodegeneration><neurodegenerative><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuron toxicity><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuronal survival><neuronal toxicity><neuroplastic><neuroplasticity><neuroprotection><neuroprotective><neurotoxicity><new approaches><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><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><peptide mimetic><peptide mimic><peptidomimetics><phospho-proteomics><phosphoproteomics><postsynaptic><pre-clinical><pre-clinical development><preclinical><preclinical development><prevent><preventing><primary degenerative dementia><receptor><response><screening><screenings><senile dementia of the Alzheimer type><simulation><skin-derived antileukoproteinase><small molecule><soluble amyloid precursor protein><stroked><strokes><therapeutic agent development><therapeutic candidate><therapeutic development><traumatic brain damage><vesicular acetylcholine transporter>