- Email: [email protected]
Minocycline modulates the neuroprotective effect of coenzyme q10 against amyloid beta 1-42 induced cognitive dysfunction in rats: Behavioral and biochemical evidence
Poster Presentations: P3
must be exported to the peripheral circulation. The conversion to 24-hydroxycholesterol, (24-0Hchol) by the key neuronal enzyme cholesterol 24-hydroxylase (CYP46A1), represents the main mechanism by which cholesterol in excess is eliminated from the brain. Methods: Since there is currently no molecule able to increase CYP46A1 activity and cross the BBB, we propose to directly overexpress CYP46A1 by administrating in the brain an AAV vector carrying the CYP46A1 cDNA. In order to find the optimal vector, we compared CYP46A1 overexpression in the hippocampus of C57Bl6/J mice by mean of stereotactic injection of several AAV serotypes: AAV5, AAV9 and AAVrh10. Results: Immunohistochemistry and western-blot revealed that hippocampal overexpression of CYP46A1 by means of AAV9 or AAVrh10 had similar patterns of expression. Moreover, it resulted in a more neuronal widespread distribution and robust CYP46A1 expression compared to AAV5. Western-blot analysis also revealed that CYP46A1 expression was w3-fold higher with AAV9 and AAVrh10 compared to AAV5. The functionality of these vectors was assessed by mass spectroscopy that demonstrated significant increase in 24-0Hchol levels in mouse hippocampus transduced with AAV9 and AAVrh10 compared to AAV5. In a therapeutic angle, we overexpressed CYP46A1 (or a control vector) by mean of an AAV9 in the hippocampus of 2.5month-old (after onset of plaques formation) APP/PS1 knock-in mice. Four months post-injection we observed that CYP46A1 overexpression induced a significant decrease in Ab-peptides and mild reduction of amyloid plaques. Furthermore, levels of GFAP and SMI-25 proteins were decreased suggesting reduced inflammation. This was complemented in an alternative mouse model of AD (APP23). CYP46A1 was overexpressed in the hippocampus of 3-months-old APP23 mice. Behavioral assessment using the Morris-water-maze and the openfield tests revealed that CYP46A1 overexpression rescued memory deficits as well as ameliorated spontaneous behavior, nine months post-injection. Conclusions: These data strongly suggest CYP46A1 as a relevant target for AD.
P3-318
THE EFFECT OF AEROBIC EXERCISE ON FALL RISK REDUCTION AMONG OLDER ADULTS WITH MILD VASCULAR COGNITIVE IMPAIRMENT
Ryan S. Falck, Lisanne ten Brinke, Ging-Yuek Robin Hsiung, Janice J. Eng, Michelle Munkacsy, Winnie Cheung, Claudia Jacova, Jennifer Davis, Teresa Liu-Ambrose, Elizabeth Dao, University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: Subcortical vascular ischaemia (SVCI) is the second most common etiology contributing to cognitive impairment among older adults. Specifically, SVCI it is characterized by impairment of executive functions and white matter lesions, consequently, individuals with SVCI are at particular risk for falls. Research suggests that exercise can reduce falls risk while augmenting executive functions. In fact, improved cognitive function may be an important yet under-appreciated mechanism by which exercise reduces falls in older adults. However, to date, very few studies have examined whether exercise could reduce falls risk among older adults with SVCI. Thus, the purpose of this randomized controlled trial was to determine if thriceweekly aerobic exercise training (AE) has benefit for falls risk and whether reduced falls risk is associated with improved cognitive function. Methods: Seventy-one older adults (56-96
P759
years) with SVCI were recruited to participate in this 6 month trial. The primary outcome for this study was the Alzheimer’s Disease Assessment Scale (ADAS-Cog). Falls risk was assessed by the Physiological Profile Assessment (PPA). All outcomes were assessed at baseline and at trial completion (i.e., 6 months). Participants were randomized (1:1) to one of two experimental groups: 1) 3x/week AE or 2) usual care (UC). Between-group differences in in falls risk (PPA z-score) at trial completion was assessed with analysis of covariance (ANCOVA), controlling for baseline PPA z-score. Bivariate analysis between changes in PPA z-score and changes in ADAS-Cog score were then performed. Results: A total of 62 participants completed the study (34 AE; 28 UC). There were no between-group differences at baseline. At trial completion, compared with the UC group, falls risk was significantly reduced among participants of the AE group (p<0.05). In addition, reduced falls risk were associated with improved cognitive function, as measured by the ADAS-Cog (r¼ -0.31; p<0.05). Conclusions: Six months of 3x/week AE training was effective at reducing falls risk among older adults with SVCI> In addition, reduced falls risk was associated with improved cognitive function. Our results support the proposed central benefit model for falls prevention, such that exercise may reduce falls risk via improved cognitive function.
P3-319
MINOCYCLINE MODULATES THE NEUROPROTECTIVE EFFECT OF COENZYME Q10 AGAINST AMYLOID BETA 1-42 INDUCED COGNITIVE DYSFUNCTION IN RATS: BEHAVIORAL AND BIOCHEMICAL EVIDENCE
Arti Singh, Punjab University, Chandigarh, India. Contact e-mail: [email protected] Background: The aim of the study was to investigate the neuro-
protective effect of CoQ10 and its modulation through minocycline against Ab(1-42) induced cognitive dysfunction and biochemical alterations in hippocampus and cerebral cortex of rats. Methods: Male SD rat were received bilateral, intrahippocampus Ab(1-42) [1mg/ml] injection. Galantamine (2 mg//kg), CoQ10 (20, 40 mg/kg), Minocycline (50 mg/kg), were administered for period of 21 days. Various behavioral parameters (body weight, locomotor activity, elevated plus maze and Morris water maze) followed by biochemical estimations (LPO, GSH, Catalase, nitrite, SOD, AChE) were assessed in discrete areas of hippocampus and cortex. Results: Bilateral intrahippocampus Ab (1-42) administration significantly reduced body weight, impaired cognitive performance and oxidative damage as compared to sham treatment. CoQ10 (20, 40 mg/kg) treatment significantly attenuated body weight and improved cognitive performance in both tests (i.e. shortened transfer latency in elevated plus maze test, Morris water maze task as well as time spent in target quadrant), attenuated AChE level and oxidative damage (reduced lipid peroxidation, nitrite level and restoration of reduced GSH and Catalase activity) in both hippocampus and cortex as compared to control. Further, combination of CoQ10 (20, 40 mg/kg) with minocycline (50 mg/kg) significantly potentiated their protective effect as compared to their effect per se. Conclusions: The present study highlight the involvement of possible microglia modulatory mechanism of CoQ10 against Ab(1-42) induced cognitive dysfunction and oxidative damage.
must be exported to the peripheral circulation. The conversion to 24-hydroxycholesterol, (24-0Hchol) by the key neuronal enzyme cholesterol 24-hydroxylase (CYP46A1), represents the main mechanism by which cholesterol in excess is eliminated from the brain. Methods: Since there is currently no molecule able to increase CYP46A1 activity and cross the BBB, we propose to directly overexpress CYP46A1 by administrating in the brain an AAV vector carrying the CYP46A1 cDNA. In order to find the optimal vector, we compared CYP46A1 overexpression in the hippocampus of C57Bl6/J mice by mean of stereotactic injection of several AAV serotypes: AAV5, AAV9 and AAVrh10. Results: Immunohistochemistry and western-blot revealed that hippocampal overexpression of CYP46A1 by means of AAV9 or AAVrh10 had similar patterns of expression. Moreover, it resulted in a more neuronal widespread distribution and robust CYP46A1 expression compared to AAV5. Western-blot analysis also revealed that CYP46A1 expression was w3-fold higher with AAV9 and AAVrh10 compared to AAV5. The functionality of these vectors was assessed by mass spectroscopy that demonstrated significant increase in 24-0Hchol levels in mouse hippocampus transduced with AAV9 and AAVrh10 compared to AAV5. In a therapeutic angle, we overexpressed CYP46A1 (or a control vector) by mean of an AAV9 in the hippocampus of 2.5month-old (after onset of plaques formation) APP/PS1 knock-in mice. Four months post-injection we observed that CYP46A1 overexpression induced a significant decrease in Ab-peptides and mild reduction of amyloid plaques. Furthermore, levels of GFAP and SMI-25 proteins were decreased suggesting reduced inflammation. This was complemented in an alternative mouse model of AD (APP23). CYP46A1 was overexpressed in the hippocampus of 3-months-old APP23 mice. Behavioral assessment using the Morris-water-maze and the openfield tests revealed that CYP46A1 overexpression rescued memory deficits as well as ameliorated spontaneous behavior, nine months post-injection. Conclusions: These data strongly suggest CYP46A1 as a relevant target for AD.
P3-318
THE EFFECT OF AEROBIC EXERCISE ON FALL RISK REDUCTION AMONG OLDER ADULTS WITH MILD VASCULAR COGNITIVE IMPAIRMENT
Ryan S. Falck, Lisanne ten Brinke, Ging-Yuek Robin Hsiung, Janice J. Eng, Michelle Munkacsy, Winnie Cheung, Claudia Jacova, Jennifer Davis, Teresa Liu-Ambrose, Elizabeth Dao, University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: Subcortical vascular ischaemia (SVCI) is the second most common etiology contributing to cognitive impairment among older adults. Specifically, SVCI it is characterized by impairment of executive functions and white matter lesions, consequently, individuals with SVCI are at particular risk for falls. Research suggests that exercise can reduce falls risk while augmenting executive functions. In fact, improved cognitive function may be an important yet under-appreciated mechanism by which exercise reduces falls in older adults. However, to date, very few studies have examined whether exercise could reduce falls risk among older adults with SVCI. Thus, the purpose of this randomized controlled trial was to determine if thriceweekly aerobic exercise training (AE) has benefit for falls risk and whether reduced falls risk is associated with improved cognitive function. Methods: Seventy-one older adults (56-96
P759
years) with SVCI were recruited to participate in this 6 month trial. The primary outcome for this study was the Alzheimer’s Disease Assessment Scale (ADAS-Cog). Falls risk was assessed by the Physiological Profile Assessment (PPA). All outcomes were assessed at baseline and at trial completion (i.e., 6 months). Participants were randomized (1:1) to one of two experimental groups: 1) 3x/week AE or 2) usual care (UC). Between-group differences in in falls risk (PPA z-score) at trial completion was assessed with analysis of covariance (ANCOVA), controlling for baseline PPA z-score. Bivariate analysis between changes in PPA z-score and changes in ADAS-Cog score were then performed. Results: A total of 62 participants completed the study (34 AE; 28 UC). There were no between-group differences at baseline. At trial completion, compared with the UC group, falls risk was significantly reduced among participants of the AE group (p<0.05). In addition, reduced falls risk were associated with improved cognitive function, as measured by the ADAS-Cog (r¼ -0.31; p<0.05). Conclusions: Six months of 3x/week AE training was effective at reducing falls risk among older adults with SVCI> In addition, reduced falls risk was associated with improved cognitive function. Our results support the proposed central benefit model for falls prevention, such that exercise may reduce falls risk via improved cognitive function.
P3-319
MINOCYCLINE MODULATES THE NEUROPROTECTIVE EFFECT OF COENZYME Q10 AGAINST AMYLOID BETA 1-42 INDUCED COGNITIVE DYSFUNCTION IN RATS: BEHAVIORAL AND BIOCHEMICAL EVIDENCE
Arti Singh, Punjab University, Chandigarh, India. Contact e-mail: [email protected] Background: The aim of the study was to investigate the neuro-
protective effect of CoQ10 and its modulation through minocycline against Ab(1-42) induced cognitive dysfunction and biochemical alterations in hippocampus and cerebral cortex of rats. Methods: Male SD rat were received bilateral, intrahippocampus Ab(1-42) [1mg/ml] injection. Galantamine (2 mg//kg), CoQ10 (20, 40 mg/kg), Minocycline (50 mg/kg), were administered for period of 21 days. Various behavioral parameters (body weight, locomotor activity, elevated plus maze and Morris water maze) followed by biochemical estimations (LPO, GSH, Catalase, nitrite, SOD, AChE) were assessed in discrete areas of hippocampus and cortex. Results: Bilateral intrahippocampus Ab (1-42) administration significantly reduced body weight, impaired cognitive performance and oxidative damage as compared to sham treatment. CoQ10 (20, 40 mg/kg) treatment significantly attenuated body weight and improved cognitive performance in both tests (i.e. shortened transfer latency in elevated plus maze test, Morris water maze task as well as time spent in target quadrant), attenuated AChE level and oxidative damage (reduced lipid peroxidation, nitrite level and restoration of reduced GSH and Catalase activity) in both hippocampus and cortex as compared to control. Further, combination of CoQ10 (20, 40 mg/kg) with minocycline (50 mg/kg) significantly potentiated their protective effect as compared to their effect per se. Conclusions: The present study highlight the involvement of possible microglia modulatory mechanism of CoQ10 against Ab(1-42) induced cognitive dysfunction and oxidative damage.