TY - JOUR
T1 - Eicosapentaenoic Acid Protects against Metabolic Impairments in the APPswe/PS1dE9 Alzheimer's Disease Mouse Model
AU - Yavari, Mahsa
AU - Ramalingam, Latha
AU - Harris, Breanna N.
AU - Kahathuduwa, Chanaka Nadeeshan
AU - Chavira, Angela
AU - Biltz, Caroline
AU - Mounce, Logan
AU - Maldonado, Kaylee Alers
AU - Scoggin, Shane
AU - Zu, Yujiao
AU - Kalupahana, Nishan Sudheera
AU - Yosofvand, Mohammad
AU - Moussa, Hanna
AU - Moustaid-Moussa, Naima
N1 - Funding Information:
As expected, serum Aβ1-40 and Aβ1-42 levels were higher in the TG group compared to WT groups in both males and females. Aβ1-40 and Aβ1-42 showed only trending increases in the HF-fed group compared to LF, which may be linked to low-grade inflammation caused by obesity, which may increase Aβ aggregation [34,64]. It is possible that longer feeding periods are required in our studies to see more significant effects of EPA on amyloids. Further, Aβ1-40 was significantly decreased by EPA in TG males but not in females compared to HF-fed mice. Based on previous research, fish oil inhibited β- and γ-secretase activity, thereby reducing amyloidogenic cleavage of APP and decreasing Aβ in female APP/PS1 TG mice [29]. Thus, it is plausible that EPA may help reduce the risk for AD through reduction of inflammation and adiposity [65]. The above mentioned beneficial effect of EPA in reducing the Aβ depositions was supported by the quantitative IHC data, reported by observed trends toward lower area of Aβ plaques in brains of TG mice treated with EPA compared to LF- and HF-fed groups. Unexpectedly, the Aβ density in LF-fed TG groups was remarkably higher than that of HF-fed groups, which may be because of the higher carbohydrates (70%) in LF diet than the HF and HF + EPA diet groups (35% carbohydrate). Indeed, Yeh et al. [66] reported that compared to a normal unpurified diet containing 50% of kcal from carbohydrates, the high carbohydrate diets (67.3% carbohydrates) significantly increased cortical protein levels of Aβ in APP/PS1 TG mice. The other reason could be that, in our IHC experiments, we used antibodies against Aβ1-16, which is the non-toxic form of Aβ [67], and further brain analyses are required using different type of antibodies against Aβ peptides to confirm differences among dietary interventions.Taken together, our results demonstrate that the HF diet increased metabolic risk factors compared with the LF diet and showed trends in increasing serum Aβ. Male mice gained more weight and fat compared to females and had higher serum leptin and insulin. EPA reduced Aβ1-40 and altered adipokines, including reducing leptin and increasing adiponectin in serum. Our findings provide evidence that dietary approaches, such as omega-3 fatty acids may effectively protect against obesity-related AD in amyloidogenic models. Our studies warrant further investigations of mechanisms underlying associations between EPA, Aβ, and adipokines in AD and tissue-specific differences. Given the current use of high doses of fish oil and EPA in hypertriglyceridemia, our findings support future clinical studies to determine the potential benefits of EPA and fish oil in AD.The research leading to these results was funded by the NIH National Center for Complementary and Integrated Health (NCCIH) and a Supplement from the National Institute on Aging (NIA) (R15 AT008879-01A1S1).
Funding Information:
The research leading to these results was funded by the NIH National Center for Complementary and Integrated Health (NCCIH) and a Supplement from the National Institute on Aging (NIA) (R15 AT008879-01A1S1).
Publisher Copyright:
© 2023 American Society for Nutrition
PY - 2023/4
Y1 - 2023/4
N2 - Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid-β (Aβ) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. Objectives: We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Aβ accumulation in AD amyloidogenic mice. Methods: Two-mo-old APPswe/PS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or EPA (36 g/kg)-supplemented HF diets. Body composition, glucose tolerance, and energy expenditure were measured, and serum and brain metabolic markers were tested 38 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. Results: HF-fed males gained more weight than females (Δ = 61 mg; P < 0.001). Compared with LF, HF increased body weights of wild-type (WT) males (Δ = 31 mg; P < 0.001). EPA reduced HF-induced weight gain in WT males (Δ = 24 mg; P = 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (Δ = −1.31 g/dL; P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (Δ = −2.51 g/mL and Δ = −0.694 ng/mL, respectively compared with HF, P ≤ 0.05) and increasing adiponectin (Δ = 21.6 ng/mL; P < 0.001). As we expected, TG mice expressed higher serum and brain Aβ than WT mice (Δ = 0.131 ng/mL; P < 0.001 and Δ = 0.56%; P < 0.01, respectively), and EPA reduced serum Aβ1-40 in TG males compared with HF (Δ = 0.053 ng/mL; P ≤ 0.05). Conclusions: To our knowledge, this is the first report that EPA reduces serum Aβ1-40 in obese AD male mice, warranting further investigations into tissue-specific mechanisms of EPA in AD.
AB - Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid-β (Aβ) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. Objectives: We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Aβ accumulation in AD amyloidogenic mice. Methods: Two-mo-old APPswe/PS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or EPA (36 g/kg)-supplemented HF diets. Body composition, glucose tolerance, and energy expenditure were measured, and serum and brain metabolic markers were tested 38 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. Results: HF-fed males gained more weight than females (Δ = 61 mg; P < 0.001). Compared with LF, HF increased body weights of wild-type (WT) males (Δ = 31 mg; P < 0.001). EPA reduced HF-induced weight gain in WT males (Δ = 24 mg; P = 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (Δ = −1.31 g/dL; P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (Δ = −2.51 g/mL and Δ = −0.694 ng/mL, respectively compared with HF, P ≤ 0.05) and increasing adiponectin (Δ = 21.6 ng/mL; P < 0.001). As we expected, TG mice expressed higher serum and brain Aβ than WT mice (Δ = 0.131 ng/mL; P < 0.001 and Δ = 0.56%; P < 0.01, respectively), and EPA reduced serum Aβ1-40 in TG males compared with HF (Δ = 0.053 ng/mL; P ≤ 0.05). Conclusions: To our knowledge, this is the first report that EPA reduces serum Aβ1-40 in obese AD male mice, warranting further investigations into tissue-specific mechanisms of EPA in AD.
KW - APP/PS1 mouse model
KW - Alzheimer's disease
KW - EPA
KW - amyloid-beta
KW - obesity
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U2 - 10.1016/j.tjnut.2023.01.030
DO - 10.1016/j.tjnut.2023.01.030
M3 - Article
C2 - 36781072
AN - SCOPUS:85150285013
SN - 0022-3166
VL - 153
SP - 1038
EP - 1051
JO - Journal of Nutrition
JF - Journal of Nutrition
IS - 4
ER -