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Small molecule BDNF mimetics
S490 S3-02-04
Symposia S3-03 Intraneuronal Ab Peptide and Progression of TAU Pathology GAMMA- SECRETASE AND SYNAPTIC PLASTICITY
Li Yueming1, Sangram Sisodia2, Kwangwook Ahn2, 1Memorial Sloan-Kettering Cancer Center, NewYork, N.Y., United States; 2University of Chicago, Chicago, Illinois, United States. Background: Gamma-secretase is an intramembranal protease that cleaves the amyloid precursor protein (APP) and other type I membrane proteins. Recent clinical studies have indicated that development of gamma-secretase based therapies has been a tremendous challenge that requires the targeting of a pathogenic proteolysis without affecting the overall processing and function of the gamma-secretase substrates. A comprehensive understanding of the regulation and function of gamma-secretase could lead to more effective treatments of Alzheimer’s disease (AD) and other human disorders. Methods: Recently, we have developed a series of chemical probes, assays and reconstitution systems that allow an in depth examination of the regulatory mechanism of gamma-secretase. We have applied these approaches in determining the mechanism of gamma-secretase modulation and elucidating the molecular basis of presenilin mutations. Results: Perturbations to gamma-secretase complex equilibrium can have a profound effect on enzyme activity and specificity. Activated PS1 is catalytically competent and the bimolecular interaction of PS1 and PEN2 is sufficient to promote endoproteolysis and catalytic activation of PS1. Conclusions: These studies contribute to our understanding of the function of PS1 with respect to gamma-secretase and presenilinase activity, insights that offer opportunities to investigate the reaction mechanism of gamma-secretase at both molecular and atomic levels. S3-02-05
CNTF PEPTIDERGIC DRUGS: A PHARMACOLOGICAL APPROACH TO ENHANCE NEUROGENESIS, NEURONAL PLASTICITY AND COGNITION
Julie Blanchard, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, N.Y., United States. Background: To date, most efforts have been directed toward inhibition of degeneration targeting Aß and/or Tau clearance but no successful drug has come to light as yet. Recently, several studies demonstrated decisive interest in regenerative approaches as a new therapeutic strategy for neurodegenerative diseases. Although, administration of neurotrophins or neural stem cells transplantation did not cause any significant reduction of Aß and Tau pathologies, such treatment demonstrated significant potential for trophic-based therapy to mend memory circuits damaged in AD. Our objective was to assess whether CNTF-based peptides can rehabilitate cognitive function and patch up neuronal network damaged by neurodegenerative conditions by enriching the brain biochemical milieu to correct altered brain homeostasis. Methods: We designed and synthesized several peptides from a biologically active region of human CNTF. To evaluate potential effects of these peptides on neurodegenerative-induced impairments, we chronically treated animals exhibiting neurodegenerative pathophysiological and cognitive disorders. Results: We found that these peptides rescued cognitive impairments in different animal models for neurodegenerative diseases (i.e. Alzheimer’s disease and Down syndrome) and increased neuronal plasticity in the brain as well as corrected abnormalities of neural stem cell proliferation. The treatment with CNTF-based peptides did not induce undesirable side effects and did not show any detectable effects on Aß and tau pathologies. Conclusions: These results add more evidence to the potential for neurotrophin-based therapy for AD and show that CNTF-based peptides can rehabilitate cognitive function, enhancing synaptic density and correcting neural progenitor cells alterations without reducing the numbers of plaques and tangles. S3-02-06
SMALL MOLECULE BDNF MIMETICS
Stephen Massa, University of California San Francisco, San Francisco, Calif., United States.
Background: The activation of the TrkB receptor tyrosine kinase by BrainDerived Neurotrophic Factor (BDNF) regulates neuronal plasticity and survival, and virally-mediated BDNF expression and exogenous BDNF protein delivery promote synaptic integrity and improve behavior in models of aging and Alzheimer’s disease (AD). In prior work, since the pharmacokinetic profile of BDNF protein is not conducive to drug development, we undertook identification of small molecule activators of TrkB signaling. Using BDNF loop 2 as a model for virtual compound library screening and following with cell-based screening, we found a group of chemically diverse compounds (LM22A1-4) that: promoted hippocampal neuron survival with nanomolar potency; activated TrkB, but not TrkA or C; and, upregulated ERK and AKT activation in vitro. LM22A-4 was further shown to: bind to TrkB; activate in vivo hippocampal and striatal TrkB, ERK and AKT and improve motor learning following traumatic brain injury when given intranasally (IN). In addition, the compound inhibited death of hippocampal neurons in culture exposed to Aß oligomers. Methods: To continue to search for compounds with enhanced pharmacologic properties, LM22A structures were used as models to search an w10 million compound library for compounds of similar pharmacophoric structure. Screening in primary hippocampal cultures revealed another group of survival-promoting compounds with similar effects on TrkB-related signaling. The effects of one of these second generation compounds (BD2-A) on pathology and learning deficits have been evaluated in a mouse AD model. Results: BD2-A (administered intraperitoneally and IN) restored neurite length and spine density in the hippocampi of APP (London/Swedish) mutant mice, and significantly improved their performance in the Y maze task. Conclusions: Small BDNF-mimetic compounds may have effects similar to BDNF in vivo, biasing signaling toward cell survival, and maintenance of neuritic structure and plasticity. These results suggest that these compounds or their derivatives may be useful in the treatment of Alzheimer’s and other neurodegenerative diseases. TUESDAY, JULY 19, 2011 SYMPOSIA S3-03 INTRANEURONAL Ab PEPTIDE AND PROGRESSION OF TAU PATHOLOGY S3-03-01
ALTERED PROTEIN EXPRESSION IN PYRAMIDAL NEURONS IN ALZHEIMER’S DISEASE
Lars Tjernberg, Karolinska Institutet, Alzheimer’s Disease Reserach Center, Huddinge, Sweden. Background: Alzheimer’s disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles, and a loss of synapses and neurons. The pathogenesis in AD is not fully understood, but it is clear that especially pyramidal neurons are affected. Previous studies aimed at finding proteins involved in the pathogenesis of AD were performed using pieces of brain tissue containing a variety of cell types and extracellular proteins. Thus, we wanted to specifically analyze alterations in pyramidal cells from postmortem human brain. Methods: We used laser capture microdissection (LCM) to isolate selected neurons, and 18O-labelling-mass spectrometry (MS) to identify proteins and calculate their relative expression in AD compared to controls. Results: We could identify and calculate the relative expression levels of 150 proteins, and many of them showed an altered expression in AD. The differently expressed proteins are involved in transcription and nucleotide binding, glycolysis, microtubule stabilization, axonal transport or inflammation. Some of these have previously been reported to be involved in AD and other neurodegenerative disorders, but several are completely novel to AD. Immunohistochemistry was performed to confirm the altered expression levels, and showed in many AD cases a pathological pattern. We also analyzed hippocampal sections by western blot, and show that such analysis can be misleading. Conclusions: We have identified several proteins that are differently regulated in pyramidal neurons in AD compared to controls, and thus could be of importance for the pathogenesis in AD. These findings could be a starting point for further studies aimed clarifying their role in AD and whether they could be targets for the treatment of the disease. Furthermore, the present approach, highly
Symposia S3-03 Intraneuronal Ab Peptide and Progression of TAU Pathology GAMMA- SECRETASE AND SYNAPTIC PLASTICITY
Li Yueming1, Sangram Sisodia2, Kwangwook Ahn2, 1Memorial Sloan-Kettering Cancer Center, NewYork, N.Y., United States; 2University of Chicago, Chicago, Illinois, United States. Background: Gamma-secretase is an intramembranal protease that cleaves the amyloid precursor protein (APP) and other type I membrane proteins. Recent clinical studies have indicated that development of gamma-secretase based therapies has been a tremendous challenge that requires the targeting of a pathogenic proteolysis without affecting the overall processing and function of the gamma-secretase substrates. A comprehensive understanding of the regulation and function of gamma-secretase could lead to more effective treatments of Alzheimer’s disease (AD) and other human disorders. Methods: Recently, we have developed a series of chemical probes, assays and reconstitution systems that allow an in depth examination of the regulatory mechanism of gamma-secretase. We have applied these approaches in determining the mechanism of gamma-secretase modulation and elucidating the molecular basis of presenilin mutations. Results: Perturbations to gamma-secretase complex equilibrium can have a profound effect on enzyme activity and specificity. Activated PS1 is catalytically competent and the bimolecular interaction of PS1 and PEN2 is sufficient to promote endoproteolysis and catalytic activation of PS1. Conclusions: These studies contribute to our understanding of the function of PS1 with respect to gamma-secretase and presenilinase activity, insights that offer opportunities to investigate the reaction mechanism of gamma-secretase at both molecular and atomic levels. S3-02-05
CNTF PEPTIDERGIC DRUGS: A PHARMACOLOGICAL APPROACH TO ENHANCE NEUROGENESIS, NEURONAL PLASTICITY AND COGNITION
Julie Blanchard, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, N.Y., United States. Background: To date, most efforts have been directed toward inhibition of degeneration targeting Aß and/or Tau clearance but no successful drug has come to light as yet. Recently, several studies demonstrated decisive interest in regenerative approaches as a new therapeutic strategy for neurodegenerative diseases. Although, administration of neurotrophins or neural stem cells transplantation did not cause any significant reduction of Aß and Tau pathologies, such treatment demonstrated significant potential for trophic-based therapy to mend memory circuits damaged in AD. Our objective was to assess whether CNTF-based peptides can rehabilitate cognitive function and patch up neuronal network damaged by neurodegenerative conditions by enriching the brain biochemical milieu to correct altered brain homeostasis. Methods: We designed and synthesized several peptides from a biologically active region of human CNTF. To evaluate potential effects of these peptides on neurodegenerative-induced impairments, we chronically treated animals exhibiting neurodegenerative pathophysiological and cognitive disorders. Results: We found that these peptides rescued cognitive impairments in different animal models for neurodegenerative diseases (i.e. Alzheimer’s disease and Down syndrome) and increased neuronal plasticity in the brain as well as corrected abnormalities of neural stem cell proliferation. The treatment with CNTF-based peptides did not induce undesirable side effects and did not show any detectable effects on Aß and tau pathologies. Conclusions: These results add more evidence to the potential for neurotrophin-based therapy for AD and show that CNTF-based peptides can rehabilitate cognitive function, enhancing synaptic density and correcting neural progenitor cells alterations without reducing the numbers of plaques and tangles. S3-02-06
SMALL MOLECULE BDNF MIMETICS
Stephen Massa, University of California San Francisco, San Francisco, Calif., United States.
Background: The activation of the TrkB receptor tyrosine kinase by BrainDerived Neurotrophic Factor (BDNF) regulates neuronal plasticity and survival, and virally-mediated BDNF expression and exogenous BDNF protein delivery promote synaptic integrity and improve behavior in models of aging and Alzheimer’s disease (AD). In prior work, since the pharmacokinetic profile of BDNF protein is not conducive to drug development, we undertook identification of small molecule activators of TrkB signaling. Using BDNF loop 2 as a model for virtual compound library screening and following with cell-based screening, we found a group of chemically diverse compounds (LM22A1-4) that: promoted hippocampal neuron survival with nanomolar potency; activated TrkB, but not TrkA or C; and, upregulated ERK and AKT activation in vitro. LM22A-4 was further shown to: bind to TrkB; activate in vivo hippocampal and striatal TrkB, ERK and AKT and improve motor learning following traumatic brain injury when given intranasally (IN). In addition, the compound inhibited death of hippocampal neurons in culture exposed to Aß oligomers. Methods: To continue to search for compounds with enhanced pharmacologic properties, LM22A structures were used as models to search an w10 million compound library for compounds of similar pharmacophoric structure. Screening in primary hippocampal cultures revealed another group of survival-promoting compounds with similar effects on TrkB-related signaling. The effects of one of these second generation compounds (BD2-A) on pathology and learning deficits have been evaluated in a mouse AD model. Results: BD2-A (administered intraperitoneally and IN) restored neurite length and spine density in the hippocampi of APP (London/Swedish) mutant mice, and significantly improved their performance in the Y maze task. Conclusions: Small BDNF-mimetic compounds may have effects similar to BDNF in vivo, biasing signaling toward cell survival, and maintenance of neuritic structure and plasticity. These results suggest that these compounds or their derivatives may be useful in the treatment of Alzheimer’s and other neurodegenerative diseases. TUESDAY, JULY 19, 2011 SYMPOSIA S3-03 INTRANEURONAL Ab PEPTIDE AND PROGRESSION OF TAU PATHOLOGY S3-03-01
ALTERED PROTEIN EXPRESSION IN PYRAMIDAL NEURONS IN ALZHEIMER’S DISEASE
Lars Tjernberg, Karolinska Institutet, Alzheimer’s Disease Reserach Center, Huddinge, Sweden. Background: Alzheimer’s disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles, and a loss of synapses and neurons. The pathogenesis in AD is not fully understood, but it is clear that especially pyramidal neurons are affected. Previous studies aimed at finding proteins involved in the pathogenesis of AD were performed using pieces of brain tissue containing a variety of cell types and extracellular proteins. Thus, we wanted to specifically analyze alterations in pyramidal cells from postmortem human brain. Methods: We used laser capture microdissection (LCM) to isolate selected neurons, and 18O-labelling-mass spectrometry (MS) to identify proteins and calculate their relative expression in AD compared to controls. Results: We could identify and calculate the relative expression levels of 150 proteins, and many of them showed an altered expression in AD. The differently expressed proteins are involved in transcription and nucleotide binding, glycolysis, microtubule stabilization, axonal transport or inflammation. Some of these have previously been reported to be involved in AD and other neurodegenerative disorders, but several are completely novel to AD. Immunohistochemistry was performed to confirm the altered expression levels, and showed in many AD cases a pathological pattern. We also analyzed hippocampal sections by western blot, and show that such analysis can be misleading. Conclusions: We have identified several proteins that are differently regulated in pyramidal neurons in AD compared to controls, and thus could be of importance for the pathogenesis in AD. These findings could be a starting point for further studies aimed clarifying their role in AD and whether they could be targets for the treatment of the disease. Furthermore, the present approach, highly