SBIR-STTR Award

Inflammation and lipid metabolism are both involved in the pathobiology of neurodegeneration in Alzheimer's disease (AD). A protein known to be a prominent regulator of both pathways is leptin. Leptin shares structural and functional characteristics with cytokines and additionally, controls energy metabolism. The long isoform of the leptin receptor (Ob-Rb), is expressed abundantly in the arcuate nucleus of the hypothalamus and is associated with the control of feeding behavior. Leptin signaling is achieved through the JAK-STAT pathway, commonly used by cytokines, which triggers the transcriptional activation of a number of genes. Ob-Rb activation can mobilize a number of kinases, including MAPK and PI3K. However, the OB-Rb leptin receptor is also expressed in neurons in the CNS, including those of the hippocampus, as well as other peripheral organs and cells of the immune system. This suggests that leptin may have additional functions. In our first aim we will address the effect of leptin supplementation in Tg2576 mice, an animal model of AD and assess the behavioral and pathobiology profile of animals in collaboration with Case Western Reserve University. We will also evaluate leptin's ability to attenuate the inflammation known to take place in the aged Tg2576 mouse. In parallel we will test AICAR, an activator of JAK/STAT pathways which could mediate leptin's action and will elucidate physiological mechanisms involved in the leptin response. In the second aim the cellular mechanisms involved in mediating leptin's lipolytic and anti-amyloidogenic properties will be evaluated pharmacologically in cell cultures and focus on the involvement of AMPK, a downstream kinase. These experiments will be pivotal for the development of leptin as a clinical therapy for AD as well as for the discovery of novel therapeutics. There are many studies that demonstrate a significant negative correlation between plasma leptin levels and incidence of dementia, in accord with the finding that AD patients experience weight loss. Thus, leptin may be a useful biomarker for disease stage and/or identifying those at risk as well as a useful therapy. As an aim for the future, we propose to identify a small group of AD patients with very low leptin levels or mildly cognitively impaired individuals with low leptin levels and a family history of AD. These subjects may enroll in our proof of concept clinical study, based on the hypothesis that they are most likely to benefit from a leptin augmentation intervention or therapy for AD. To that end, we have engaged prominent clinical consultants to assist us with the planning stages. Leptin, an endogenous peptide native to the endocrine system, was first discovered and patented by Professor Jeffrey Friedman of Rockefeller University in 1994. While the peptide demonstrated both favorable pharmacological properties and safety profile in Clinical Trials, it failed to demonstrate efficacy for the targeted condition (obesity). Seminal preclinical research conducted by Neurotez's founder, Nikolaos Tezapsidis and his team, was published in December 2004, showing that leptin augmentation therapy substantially reduced the brain levels of amyloid beta ("Aa") in mouse models. Circulating leptin levels decline in most AD patients proportionally to cognitive deterioration. Therefore, Neurotez believes that therapy with recombinant human leptin should be beneficial to AD patients, both, as an anti-Aa agent, and, as bonus benefit, as an insulin sensitizer.

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Inflammation and lipid metabolism are both involved in the pathobiology of neurodegeneration in Alzheimer's disease (AD). A protein known to be a prominent regulator of both pathways is leptin. Leptin shares structural and functional characteristics with cytokines and additionally, controls energy metabolism. The long isoform of the leptin receptor (Ob-Rb), is expressed abundantly in the arcuate nucleus of the hypothalamus and is associated with the control of feeding behavior. Leptin signaling is achieved through the JAK-STAT pathway, commonly used by cytokines, which triggers the transcriptional activation of a number of genes. Ob-Rb activation can mobilize a number of kinases, including MAPK and PI3K. However, the OB-Rb leptin receptor is also expressed in neurons in the CNS, including those of the hippocampus, as well as other peripheral organs and cells of the immune system. This suggests that leptin may have additional functions. In our first aim we will address the effect of leptin supplementation in Tg2576 mice, an animal model of AD and assess the behavioral and pathobiology profile of animals in collaboration with Case Western Reserve University. We will also evaluate leptin's ability to attenuate the inflammation known to take place in the aged Tg2576 mouse. In parallel we will test AICAR, an activator of JAK/STAT pathways which could mediate leptin's action and will elucidate physiological mechanisms involved in the leptin response. In the second aim the cellular mechanisms involved in mediating leptin's lipolytic and anti-amyloidogenic properties will be evaluated pharmacologically in cell cultures and focus on the involvement of AMPK, a downstream kinase. These experiments will be pivotal for the development of leptin as a clinical therapy for AD as well as for the discovery of novel therapeutics. There are many studies that demonstrate a significant negative correlation between plasma leptin levels and incidence of dementia, in accord with the finding that AD patients experience weight loss. Thus, leptin may be a useful biomarker for disease stage and/or identifying those at risk as well as a useful therapy. As an aim for the future, we propose to identify a small group of AD patients with very low leptin levels or mildly cognitively impaired individuals with low leptin levels and a family history of AD. These subjects may enroll in our proof of concept clinical study, based on the hypothesis that they are most likely to benefit from a leptin augmentation intervention or therapy for AD. To that end, we have engaged prominent clinical consultants to assist us with the planning stages. Leptin, an endogenous peptide native to the endocrine system, was first discovered and patented by Professor Jeffrey Friedman of Rockefeller University in 1994. While the peptide demonstrated both favorable pharmacological properties and safety profile in Clinical Trials, it failed to demonstrate efficacy for the targeted condition (obesity). Seminal preclinical research conducted by Neurotez's founder, Nikolaos Tezapsidis and his team, was published in December 2004, showing that leptin augmentation therapy substantially reduced the brain levels of amyloid beta ("Aa") in mouse models. Circulating leptin levels decline in most AD patients proportionally to cognitive deterioration. Therefore, Neurotez believes that therapy with recombinant human leptin should be beneficial to AD patients, both, as an anti-Aa agent, and, as bonus benefit, as an insulin sensitizer.

Thesaurus Terms:
Alzheimer's Disease, Leptin Aging, Base, Behavior, Bioenergetics, Biomarker, Brain, Cell, Cholesterol, Clinical Trial, Complement, Concept, Conditioning, Cortisol, Cytokine, Dementia, Density, Disease /Therapy Duration, Dosage, Endocrine Gland /System, Experience, Family, Gene, Growth Factor, Hippocampus, Human, Hypothalamus, Immune System, Inflammation, Insulin, Interferon, Lipid Metabolism, Model, Neural Degeneration, Neuron, Obesity, Organ, Pathology, Peptide, Performance, Plasma, Protein, Protein Kinase, Receptor, Sectioning, Teacher, Therapy, Tissue /Cell Culture, Triglyceride, University, Weight Loss