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Innate immunity stimulation as a novel therapeutic approach in Alzheimer's disease
P392
Poster Presentations: P2
Figure 1. Interaction of mean scores of the RBMT groups of active and sham rTMS over the measurement instants T0, T1 and T2. Effect of time: T0-T1. Interaction: T0-T1.
trial was associated with severe adverse effects in a minority of patients. Our research group postulated stimulation of the innate immune system, via the Toll-like receptor 9 (TLR9), as a possible alternative method for ameliorating AD pathology, without associated toxicity. A significant concern with immunotherapy is clearance of vascular amyloid and associated microhemorrhages. This is an important issue, since cerebral amyloid angiopathy (CAA) is a common feature in AD and cognitively normal elderly individuals. We tested the efficacy of TLR9 signaling stimulation for reducing parenchymal and vascular amyloid, as well as tau related pathology. Methods: We utilized TLR9 agonist type B CpG oligonucleotides (ODNs) to stimulate innate immunity in 3xTg-AD mice, which develop both plaque and tangle pathology, and in Tg-SwDI mice with extensive CAA. Animals were divided into 2 study groups treated prior to or after the onset of AD pathology. Results: After treatment the mice were behaviorally tested. No statistical differences were observed between the groups in any of the locomotor parameters measured. CpG ODN treatment improved working memory in 3xTg-AD mice as indicated by radial arm maze testing. TLR9 stimulation was also effective at improving short-term memory in Tg-SwDI mice as evidenced by novel-object recognition testing. In 3xTg-AD mice TLR9 signaling reduced both amyloid deposits and hyperphosphorylated tau pathology. Semiquantitative analysis of hippocampal CA1 neurons revealed reduction in AT8 and PHF1 immunoreactivity in CpG ODN-treated 3xTg-AD mice. The reduction of plaque and tangle pathology was paralleled by an overall reduction in the numbers of activated microglia. There were no group differences in the levels of CNS astrocytosis; hence there was no evidence of encephalitis in the brains of treated mice. Further histological, biochemical analyses and characterization of immune responses are ongoing. Conclusions: Overall, stimulation of the TLR9 and thus innate immunity with CpG ODN (currently used in clinical trials for a variety of other diseases) represents a novel immunotherapeutic approach for AD.
P2-369
NEUROGENIC EFFECTS OF THE GALANTAMINE PRODRUG, GLN-1062
Jackalina Van Kampen1, Denis Kay1, Dave Baranowski2, Alfred Maelicke3, Andreas Kopke3, 1Neurodyn Inc., Charlottetown, Prince Edward Island, Canada; 2Neurodyn Inc., Charlottetown, Prince Edward Island, Canada; 3Galantos Pharma, Mainz, Germany.
Figure 2. Interaction of mean scores of the Stroop test / rectangles over the measurement instants T0, T1 and T2. Effect of time: T0-T1. Interaction: T0T1. not on Stroop. Conclusions: Although sample size is still statistically limiting, the results suggest cognitive response in memory and attention to high-frequency rTMS, and a sustained effect in memory after one month.
P2-368
INNATE IMMUNITY STIMULATION AS A NOVEL THERAPEUTIC APPROACH IN ALZHEIMER’S DISEASE
Henrieta Scholtzova1, Fernando Goni2, Jason Pan2, Yanjie Sun2, Jialin Li2, Pankaj Mehta3, Thomas Wisniewski2, 1NYU School of Medicine, New York, New York, United States; 2NYU School of Medicine, New York, New York, United States; 3Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States. Background: Alzheimer’s disease (AD) is the most common cause of dementia and has a major societal and economic impact. Immunomodulation has shown great promise as an AD therapy, even though the initial clinical
Background: The potential of cholinergic drugs for the treatment of dementia may go beyond simply regulating neurotransmitter levels. With the discovery of ongoing neurogenesis in the adult brain comes new insights into potential therapies. A simple shift in the balance between cell generation and cell loss may slow disease progression and possibly even reverse existing cognitive deficits. One potential neurogenic regulator may be acetylcholine, itself, which has been shown to play a critical role in cortical and hippocampal development. In the adult, removal of acetylcholine inputs dramatically impairs neurogenesis in these regions and it has been thought that the cognitive deficits associated with dementia may result, in part, from resulting reduced cell turnover. A significant induction of hippocampal neurogenesis in the adult ratbrain can be triggered following treatment with various cholinergic drugs, including cholinesterase inhibitors. Galantamine may be particularly effective due to allosteric actions at nicotinic receptors. Here, we report the neurogenic effects GLN-1062, a prodrug of galantamine designed to provide improved blood brain barrier penetration, greater potency, and fewer side effects than the cholinesterase inhibitors currently used for the treatment of Alzheimer’s disease and other dementias. Methods: Male Sprague Dawley rats received twice daily intranasal delivery of either saline (0.9%) or 0.3, 1, or 3 mg/kg GLN-1062 for two weeks. Another cohort of animals received twice daily oral administration of either sterile water, 0.3 mg/kg donepezil (Aricept) or 3 mg/kg galantamine. During this time, animals also received daily injections of the cell proliferation marker, bromodeoxyuridine (BrdU). Results: GLN-1062 induced a significant increase in the number of newly-generated cells in the dentate gyrus and CA1 regions of the hippocampus. Oral delivery of donepezil failed to induce cell proliferation in either region of the hippocampus. GLN-1062 induced a significantly greater increase in hippocampal BrdU-positive cells
Poster Presentations: P2
Figure 1. Interaction of mean scores of the RBMT groups of active and sham rTMS over the measurement instants T0, T1 and T2. Effect of time: T0-T1. Interaction: T0-T1.
trial was associated with severe adverse effects in a minority of patients. Our research group postulated stimulation of the innate immune system, via the Toll-like receptor 9 (TLR9), as a possible alternative method for ameliorating AD pathology, without associated toxicity. A significant concern with immunotherapy is clearance of vascular amyloid and associated microhemorrhages. This is an important issue, since cerebral amyloid angiopathy (CAA) is a common feature in AD and cognitively normal elderly individuals. We tested the efficacy of TLR9 signaling stimulation for reducing parenchymal and vascular amyloid, as well as tau related pathology. Methods: We utilized TLR9 agonist type B CpG oligonucleotides (ODNs) to stimulate innate immunity in 3xTg-AD mice, which develop both plaque and tangle pathology, and in Tg-SwDI mice with extensive CAA. Animals were divided into 2 study groups treated prior to or after the onset of AD pathology. Results: After treatment the mice were behaviorally tested. No statistical differences were observed between the groups in any of the locomotor parameters measured. CpG ODN treatment improved working memory in 3xTg-AD mice as indicated by radial arm maze testing. TLR9 stimulation was also effective at improving short-term memory in Tg-SwDI mice as evidenced by novel-object recognition testing. In 3xTg-AD mice TLR9 signaling reduced both amyloid deposits and hyperphosphorylated tau pathology. Semiquantitative analysis of hippocampal CA1 neurons revealed reduction in AT8 and PHF1 immunoreactivity in CpG ODN-treated 3xTg-AD mice. The reduction of plaque and tangle pathology was paralleled by an overall reduction in the numbers of activated microglia. There were no group differences in the levels of CNS astrocytosis; hence there was no evidence of encephalitis in the brains of treated mice. Further histological, biochemical analyses and characterization of immune responses are ongoing. Conclusions: Overall, stimulation of the TLR9 and thus innate immunity with CpG ODN (currently used in clinical trials for a variety of other diseases) represents a novel immunotherapeutic approach for AD.
P2-369
NEUROGENIC EFFECTS OF THE GALANTAMINE PRODRUG, GLN-1062
Jackalina Van Kampen1, Denis Kay1, Dave Baranowski2, Alfred Maelicke3, Andreas Kopke3, 1Neurodyn Inc., Charlottetown, Prince Edward Island, Canada; 2Neurodyn Inc., Charlottetown, Prince Edward Island, Canada; 3Galantos Pharma, Mainz, Germany.
Figure 2. Interaction of mean scores of the Stroop test / rectangles over the measurement instants T0, T1 and T2. Effect of time: T0-T1. Interaction: T0T1. not on Stroop. Conclusions: Although sample size is still statistically limiting, the results suggest cognitive response in memory and attention to high-frequency rTMS, and a sustained effect in memory after one month.
P2-368
INNATE IMMUNITY STIMULATION AS A NOVEL THERAPEUTIC APPROACH IN ALZHEIMER’S DISEASE
Henrieta Scholtzova1, Fernando Goni2, Jason Pan2, Yanjie Sun2, Jialin Li2, Pankaj Mehta3, Thomas Wisniewski2, 1NYU School of Medicine, New York, New York, United States; 2NYU School of Medicine, New York, New York, United States; 3Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States. Background: Alzheimer’s disease (AD) is the most common cause of dementia and has a major societal and economic impact. Immunomodulation has shown great promise as an AD therapy, even though the initial clinical
Background: The potential of cholinergic drugs for the treatment of dementia may go beyond simply regulating neurotransmitter levels. With the discovery of ongoing neurogenesis in the adult brain comes new insights into potential therapies. A simple shift in the balance between cell generation and cell loss may slow disease progression and possibly even reverse existing cognitive deficits. One potential neurogenic regulator may be acetylcholine, itself, which has been shown to play a critical role in cortical and hippocampal development. In the adult, removal of acetylcholine inputs dramatically impairs neurogenesis in these regions and it has been thought that the cognitive deficits associated with dementia may result, in part, from resulting reduced cell turnover. A significant induction of hippocampal neurogenesis in the adult ratbrain can be triggered following treatment with various cholinergic drugs, including cholinesterase inhibitors. Galantamine may be particularly effective due to allosteric actions at nicotinic receptors. Here, we report the neurogenic effects GLN-1062, a prodrug of galantamine designed to provide improved blood brain barrier penetration, greater potency, and fewer side effects than the cholinesterase inhibitors currently used for the treatment of Alzheimer’s disease and other dementias. Methods: Male Sprague Dawley rats received twice daily intranasal delivery of either saline (0.9%) or 0.3, 1, or 3 mg/kg GLN-1062 for two weeks. Another cohort of animals received twice daily oral administration of either sterile water, 0.3 mg/kg donepezil (Aricept) or 3 mg/kg galantamine. During this time, animals also received daily injections of the cell proliferation marker, bromodeoxyuridine (BrdU). Results: GLN-1062 induced a significant increase in the number of newly-generated cells in the dentate gyrus and CA1 regions of the hippocampus. Oral delivery of donepezil failed to induce cell proliferation in either region of the hippocampus. GLN-1062 induced a significantly greater increase in hippocampal BrdU-positive cells