TY - JOUR
T1 - Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and α-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer's disease
T2 - Are combinations more effective?
AU - Sharman, Matthew J.
AU - Gyengesi, Erika
AU - Liang, Huazheng
AU - Chatterjee, Pratishtha
AU - Karl, Tim
AU - Li, Qiao Xin
AU - Wenk, Markus R.
AU - Halliwell, Barry
AU - Martins, Ralph N.
AU - Münch, Gerald
N1 - Publisher Copyright:
© 2018
PY - 2019/4
Y1 - 2019/4
N2 - Increasingly, evidence is accumulating pointing at a protective role of a healthy diet at decreasing the risk of Alzheimer's disease. To test the effectiveness of nutritional components, the following food-derived compounds: curcumin alone (curcumin), curcumin combined with (−)epigallocatechin-3-gallate (EGCG), docosahexaenoic acid (DHA) and α-lipoic acid (ALA) (curcumin + EDA), or a combination of EGCG, DHA and ALA (EDA) were assessed in male Tg2576 transgenic mice on amyloid plaque load, amyloid levels (Aβ40/Aβ42, but not oligomers due to tissue limitations), microglial activation and memory using the contextual and cued fear conditioning test. The combination diet EDA, resulted in the strongest reduction of amyloid plaque load in both the cortical (p <.0001) and hippocampal (p <.0001) areas of the Tg2576 mouse brain, along with lower Aβ40/Aβ42 levels in the frontal cortex (p =.000129 and p =.000039, respectively) and Aβ42 levels in the temporal lobe (p =.000082). A curcumin only diet was shown to lower amyloid plaque load (p =.028), but when combined with EGCG, DHA and ALA did not result in further decreases in amyloid plaque load. The EDA combination group showed the most prominent decrease in microglial activation (number of microglia around plaques: p <.05 and p <.0001, respectively, for the cortex and hippocampus). Analysing the hippocampal associated contextual fear conditioning revealed that both the curcumin+EDA (p <.0001) and EDA groups (p =.001) spent increased time on freezing compared to the control group. In addition, the curcumin+EDA group showed a significant increase in time spent freezing compared with the curcumin only group. In the amygdala associated cued test, all mice demonstrated the ability to associate the conditioned stimulus with the unconditioned stimulus as evidenced by a significant increase in freezing behaviour in response to the presentation of the cue (p <.0001). Post-hoc analysis showed that only curcumin+EDA (p <.0001) and EDA groups (p <.0001) developed a significant increase in freezing during the cue presentation. The results from this study show that the combination of EGCG, DHA and ALA (EDA) appeared to have the most potent anti-inflammatory and neuroprotective effect. Our results also demonstrate that interactions between nutraceutical products might result in counterproductive outcomes, highlighting the fact that manufacturers of nutraceuticals containing multiple compounds should be careful not to claim additive or synergistic effects of their combination products in vivo without having tested it in animal models and/or human clinical trials.
AB - Increasingly, evidence is accumulating pointing at a protective role of a healthy diet at decreasing the risk of Alzheimer's disease. To test the effectiveness of nutritional components, the following food-derived compounds: curcumin alone (curcumin), curcumin combined with (−)epigallocatechin-3-gallate (EGCG), docosahexaenoic acid (DHA) and α-lipoic acid (ALA) (curcumin + EDA), or a combination of EGCG, DHA and ALA (EDA) were assessed in male Tg2576 transgenic mice on amyloid plaque load, amyloid levels (Aβ40/Aβ42, but not oligomers due to tissue limitations), microglial activation and memory using the contextual and cued fear conditioning test. The combination diet EDA, resulted in the strongest reduction of amyloid plaque load in both the cortical (p <.0001) and hippocampal (p <.0001) areas of the Tg2576 mouse brain, along with lower Aβ40/Aβ42 levels in the frontal cortex (p =.000129 and p =.000039, respectively) and Aβ42 levels in the temporal lobe (p =.000082). A curcumin only diet was shown to lower amyloid plaque load (p =.028), but when combined with EGCG, DHA and ALA did not result in further decreases in amyloid plaque load. The EDA combination group showed the most prominent decrease in microglial activation (number of microglia around plaques: p <.05 and p <.0001, respectively, for the cortex and hippocampus). Analysing the hippocampal associated contextual fear conditioning revealed that both the curcumin+EDA (p <.0001) and EDA groups (p =.001) spent increased time on freezing compared to the control group. In addition, the curcumin+EDA group showed a significant increase in time spent freezing compared with the curcumin only group. In the amygdala associated cued test, all mice demonstrated the ability to associate the conditioned stimulus with the unconditioned stimulus as evidenced by a significant increase in freezing behaviour in response to the presentation of the cue (p <.0001). Post-hoc analysis showed that only curcumin+EDA (p <.0001) and EDA groups (p <.0001) developed a significant increase in freezing during the cue presentation. The results from this study show that the combination of EGCG, DHA and ALA (EDA) appeared to have the most potent anti-inflammatory and neuroprotective effect. Our results also demonstrate that interactions between nutraceutical products might result in counterproductive outcomes, highlighting the fact that manufacturers of nutraceuticals containing multiple compounds should be careful not to claim additive or synergistic effects of their combination products in vivo without having tested it in animal models and/or human clinical trials.
KW - Amyloid plaque
KW - Curcumin
KW - Fish oil
KW - Green tea
KW - Inflammation
KW - Lipoic acid
KW - Microglia
UR - http://www.scopus.com/inward/record.url?scp=85059703040&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2018.11.026
DO - 10.1016/j.nbd.2018.11.026
M3 - Article
C2 - 30610916
AN - SCOPUS:85059703040
SN - 0969-9961
VL - 124
SP - 505
EP - 519
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -