神经退行性病
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Figure 2｜Ketogenic diet treatment ameliorates impaired working memory and reduces amyloid deposition in the hippocampus and cortex of 6-month-old APP/PS1 mice.
The cognitive capacity of APP/PS1 mice was evaluated using the NORT test and Y-maze spontaneous alternation test after mice had been fed a KD for a period of 3 months. KD treatment resulted in a substantial increase in the recognition index of APP/PS1 mice (P < 0.001, Figure 2B), demonstrating that the new item was preferred. In contrast, CD treatment resulted in a lower ratio, which suggests that the new item was not favored. To evaluate the spatial working memory of mice, the Y-maze spontaneous alternation test was used. Despite the KD intervention group exhibited a reduction in body weight compared to in the APP/PS1 mice with CD treatment (Additional Figure 1), there was no significant difference in the total number of arm entries between the three groups (P > 0.05, Figure 2D). This demonstrates that KD did not have an effect on locomotor activity of the APP/PS1 mice. The rate of spontaneous alternation in WT mice fed a CD was significantly greater than the rate in the APP/PS1+CD group (P < 0.0001) and APP/PS1+KD group (P < 0.05, Figure 2E). The rate of spontaneous alternation was considerably higher in the KD treatment group compared with the APP/PS1+CD group (P < 0.001). In general, our findings show that a KD could alleviate the working memory deficit seen in APP/PS1 mice.
The amyloid protein is widely acknowledged as a significant contributor to the pathogenesis of AD. Aβ plaques (which are often composed of the Aβ1–42 type) are an example of a common pathogenic trait connected to AD (Caballero et al., 2020). Immunofluorescence experiments showed a much greater intensity of Aβ1–42 immunofluorescence in the brains of APP/PS1 mice than WT animals (Figure 2F and G). Compared with APP/PS1 animals with CD treatment, the Aβ plaque-positive area in the hippocampus of APP/PS1 mice with KD showed a statistically significant reduction (P < 0.0001).
Figure 3｜Ketogenic diet decreases microgliosis in 6-month-old APP/PS1 mice.
Multiple studies have shown that Aβ-induced neuroinflammation is associated with neurodegenerative processes characteristic of AD (Ardura-Fabregat et al., 2017; Anderson and Vetter, 2019), and that activation of astrocytes and microglia may contribute to disease pathogenesis. Microglial and astrocyte activity is well accepted as a measure of neuroinflammation (Wang et al., 2021). Here, immunohistochemical analysis revealed an increase in Iba1-positive microglia in APP/PS1 mice, indicating that microglia activation was higher than WT mice. Iba1-positive microglia were greatly decreased in both the cortex and the hippocampus as a result of KD, thereby reflecting less neuroinflammatory reactions. In addition, GFAP expression was upregulated in the neocortex and hippocampus of APP/PS1 model mice. However, this increase was dramatically decreased by KD therapy. According to these results, microglia and astrocyte activation are effectively suppressed by KD treatment in APP/PS1 animals (Figure 3A–D).