- Email: [email protected]
creb signaling that regulates BDNF expression downstream in rat hippocampus
P478
Poster Presentations: P1
increased levels of lysozyme in the cerebrospinal fluid and in brains from Alzheimer patients and that lysozyme co-localize with Ab in plaques from sporadic Alzheimer patients. Lysozyme prevents Ab aggregation and rescues SH-SY5Y neuroblastoma cells from Ab induced toxicity. Furthermore, lysozyme binds to Ab and this binding inhibits the cellular uptake of Ab. Conclusions: This study shows that lysozyme has protective functions in Alzheimer’s disease and points to lysozyme as a potential therapeutic to attenuate the spreading of Ab and halt the progression of AD.
P1-317
can be an attractive adjuvant therapy to improve hypertension associated impairment of cognition.
PHOSPHODIESTERASE-4 INHIBITORS ALLEVIATE HYPERTENSION-INDUCED COGNITIVE IMPAIRMENT VIA CAMP/CREB SIGNALING THAT REGULATES BDNF EXPRESSION DOWNSTREAM IN RAT HIPPOCAMPUS
Sugin L.A.L. Jabaris Sobhana George, Girish Ramesh, Saravana Babu Chidambaram, Sri Ramachandra University, Chennai, Tamil Nadu, India. Contact e-mail: [email protected] Background: Inhibition of Phosphodiesterase-4 (PDE-4) promotes cognitive functions by blocking the degradation of cAMP. Previous studies have shown that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response elementbinding protein (pCREB) and subsequent formation of BDNF. In addition, PDE-4 inhibitors have been shown to reverse memory impairment in various animal models. Here, we examined the effect of rolipram, roflumilast and clonidine on the impairment of learning and memory observed in experimentally induced hypertensive rats. We selected clonidine, centrally acting anti-hypertensive drug to evaluate whether treatment of hypertension could attenuate the cognitive impairments induced by hypertension (HT) in therapeutic model. Methods: We used DOCA salt hypertensive model to induce learning and memory deficits. Systolic blood pressure (SBP) was measured by tailcuff method. Novel object recognition task (NORT) model was used to evaluate recognition memory. Plasma and brain concentrations of rolipram, roflumilast and roflumilast N-oxide were analysed after NORT. Also, expression of protein levels of GFAP, pCREB and BDNF along with the PDE-4 subtypes (B, D) in hippocampus were quantified. Results: SBP was significantly increased in DOCA rats when compared to sham operated rats; this effect was reversed by repeated administration of clonidine (25 mg/kg, p.o), whereas PDE-4 inhibitors, rolipram (0.03, 0.1, 0.3mg/kg, i.p) and roflumilast (0.1, 0.3,1mg/kg, p.o) did not. PDE-4 inhibitors significantly improved recognition memory in NORT, while clonidine displayed less exploration in novel object. Further, both pCREB and BDNF showed decreased levels of expression and upregulation of GFAP in hypertensive rats in comparison to sham operated rats. However, continued administration of PDE-4 inhibitors showed inverse correlation with the expression of pCREB and BDNF in hypersensitive rats. In contrast, no significant changes in levels of pCREB and BDNF were observed in clonidine treatment group. Besides, rolipram, roflumilast and roflumilast N-oxide showed linear increase in plasma and brain concentrations after NORT. Reversal of cognitive deficits via CREB/ BDNF signalling was further confirmed with expression analysis of PDE-4B,D. Conclusions: These results suggest that PDE-4 inhibitors ameliorates HT-induced recognition memory functions inspite of no change in blood pressure. Therefore, PDE-4 inhibition
P1-318
INTERNET-BASED RECRUITMENT AND SCREENING OF SUBJECTS FOR AD TRIALS USING LONGITUDINAL DATA FROM THE BRAIN HEALTH REGISTRY
Michael W. Weiner1, Rachel L. Nosheny2, Derek Flennkiken3, Philip S. Insel3, Shannon Finley3, Scott Mackin4, Monica Camacho3, Diana Truran-Sacrey5, 1University of California San Francisco, San Francisco, CA, USA; 2San Francisco Veteran’s Administration Medical Center, San Francisco, CA, USA; 3San Francisco Veteran’s Administration Medical Center, San Francisco, CA, USA; 4UCSF, San Francisco, CA, USA; 5 Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA. Contact e-mail: [email protected] Background: The expense of recruiting, screening, and longitudinally-assessing subjects for Alzheimer’s disease (AD) clinical trials is a significant obstacle to developing effective treatments. Several internet-based patient registries have recently been developed to assemble trial-ready cohorts. The BrainHealthRegistry.org (BHR), launched in 2014, captures detailed, longitudinal health and lifestyle information and measures of cognitive function to facilitate AD clinical trials. Methods: BHR subjects complete questionnaires (health history, medications, memory, and family history of disease), and online neuropsychological tests (NPTs). All tasks are completed online with no supervision. Subjects are invited to return to BHR every 6 months to complete additional online tasks and repeat NPTs. We analyzed the demographic and cognitive profiles of the general BHR cohort, as well as those who completed 6-month follow up NPTs, to analyze eligibility for AD clinical trials. Results: The BHR has over 11,000 subjects. The average age of registrants is 57614.6 years, and a total of 6704 registrants are over age 55. Sixty-nine percent are female, and 13% belong to racial/ethnic minorities. For subjects over age 55 years, 3% report having dementia, and 44% report a first-degree relative with AD. Subjective memory problems were reported by 44% of older adults. Twenty-four percent of subjects over 55 score at least 1 standard deviation below the age-adjusted mean on NPTs, and 87% of those subjects also endorse a memory problem. Forty-eight percent of subjects returned to the BHR website for a 6-month follow up aimed at longitudinal data collection, and 64% of returners completed all follow-up tasks. The average age of returners is 61612.1 years, and 73% are female. Fifty-six percent of older returners endorse a memory problem, and 33% have family history of AD. Conclusions: The BHR contains a significant number of subjects who would be eligible for AD clinical trials based on demographics
Poster Presentations: P1
increased levels of lysozyme in the cerebrospinal fluid and in brains from Alzheimer patients and that lysozyme co-localize with Ab in plaques from sporadic Alzheimer patients. Lysozyme prevents Ab aggregation and rescues SH-SY5Y neuroblastoma cells from Ab induced toxicity. Furthermore, lysozyme binds to Ab and this binding inhibits the cellular uptake of Ab. Conclusions: This study shows that lysozyme has protective functions in Alzheimer’s disease and points to lysozyme as a potential therapeutic to attenuate the spreading of Ab and halt the progression of AD.
P1-317
can be an attractive adjuvant therapy to improve hypertension associated impairment of cognition.
PHOSPHODIESTERASE-4 INHIBITORS ALLEVIATE HYPERTENSION-INDUCED COGNITIVE IMPAIRMENT VIA CAMP/CREB SIGNALING THAT REGULATES BDNF EXPRESSION DOWNSTREAM IN RAT HIPPOCAMPUS
Sugin L.A.L. Jabaris Sobhana George, Girish Ramesh, Saravana Babu Chidambaram, Sri Ramachandra University, Chennai, Tamil Nadu, India. Contact e-mail: [email protected] Background: Inhibition of Phosphodiesterase-4 (PDE-4) promotes cognitive functions by blocking the degradation of cAMP. Previous studies have shown that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response elementbinding protein (pCREB) and subsequent formation of BDNF. In addition, PDE-4 inhibitors have been shown to reverse memory impairment in various animal models. Here, we examined the effect of rolipram, roflumilast and clonidine on the impairment of learning and memory observed in experimentally induced hypertensive rats. We selected clonidine, centrally acting anti-hypertensive drug to evaluate whether treatment of hypertension could attenuate the cognitive impairments induced by hypertension (HT) in therapeutic model. Methods: We used DOCA salt hypertensive model to induce learning and memory deficits. Systolic blood pressure (SBP) was measured by tailcuff method. Novel object recognition task (NORT) model was used to evaluate recognition memory. Plasma and brain concentrations of rolipram, roflumilast and roflumilast N-oxide were analysed after NORT. Also, expression of protein levels of GFAP, pCREB and BDNF along with the PDE-4 subtypes (B, D) in hippocampus were quantified. Results: SBP was significantly increased in DOCA rats when compared to sham operated rats; this effect was reversed by repeated administration of clonidine (25 mg/kg, p.o), whereas PDE-4 inhibitors, rolipram (0.03, 0.1, 0.3mg/kg, i.p) and roflumilast (0.1, 0.3,1mg/kg, p.o) did not. PDE-4 inhibitors significantly improved recognition memory in NORT, while clonidine displayed less exploration in novel object. Further, both pCREB and BDNF showed decreased levels of expression and upregulation of GFAP in hypertensive rats in comparison to sham operated rats. However, continued administration of PDE-4 inhibitors showed inverse correlation with the expression of pCREB and BDNF in hypersensitive rats. In contrast, no significant changes in levels of pCREB and BDNF were observed in clonidine treatment group. Besides, rolipram, roflumilast and roflumilast N-oxide showed linear increase in plasma and brain concentrations after NORT. Reversal of cognitive deficits via CREB/ BDNF signalling was further confirmed with expression analysis of PDE-4B,D. Conclusions: These results suggest that PDE-4 inhibitors ameliorates HT-induced recognition memory functions inspite of no change in blood pressure. Therefore, PDE-4 inhibition
P1-318
INTERNET-BASED RECRUITMENT AND SCREENING OF SUBJECTS FOR AD TRIALS USING LONGITUDINAL DATA FROM THE BRAIN HEALTH REGISTRY
Michael W. Weiner1, Rachel L. Nosheny2, Derek Flennkiken3, Philip S. Insel3, Shannon Finley3, Scott Mackin4, Monica Camacho3, Diana Truran-Sacrey5, 1University of California San Francisco, San Francisco, CA, USA; 2San Francisco Veteran’s Administration Medical Center, San Francisco, CA, USA; 3San Francisco Veteran’s Administration Medical Center, San Francisco, CA, USA; 4UCSF, San Francisco, CA, USA; 5 Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA. Contact e-mail: [email protected] Background: The expense of recruiting, screening, and longitudinally-assessing subjects for Alzheimer’s disease (AD) clinical trials is a significant obstacle to developing effective treatments. Several internet-based patient registries have recently been developed to assemble trial-ready cohorts. The BrainHealthRegistry.org (BHR), launched in 2014, captures detailed, longitudinal health and lifestyle information and measures of cognitive function to facilitate AD clinical trials. Methods: BHR subjects complete questionnaires (health history, medications, memory, and family history of disease), and online neuropsychological tests (NPTs). All tasks are completed online with no supervision. Subjects are invited to return to BHR every 6 months to complete additional online tasks and repeat NPTs. We analyzed the demographic and cognitive profiles of the general BHR cohort, as well as those who completed 6-month follow up NPTs, to analyze eligibility for AD clinical trials. Results: The BHR has over 11,000 subjects. The average age of registrants is 57614.6 years, and a total of 6704 registrants are over age 55. Sixty-nine percent are female, and 13% belong to racial/ethnic minorities. For subjects over age 55 years, 3% report having dementia, and 44% report a first-degree relative with AD. Subjective memory problems were reported by 44% of older adults. Twenty-four percent of subjects over 55 score at least 1 standard deviation below the age-adjusted mean on NPTs, and 87% of those subjects also endorse a memory problem. Forty-eight percent of subjects returned to the BHR website for a 6-month follow up aimed at longitudinal data collection, and 64% of returners completed all follow-up tasks. The average age of returners is 61612.1 years, and 73% are female. Fifty-six percent of older returners endorse a memory problem, and 33% have family history of AD. Conclusions: The BHR contains a significant number of subjects who would be eligible for AD clinical trials based on demographics