Sustained high body temperature exacerbates cognitive function and Alzheimer's disease-related pathologies

Abstract

Global warming is a serious public health threat to people worldwide. High body temperature is one of the important risk factors for Alzheimer's disease (AD), and the body temperature of AD patients has been found to be significantly higher than that of elderly control subjects. However, the effects of high body temperature on cognitive function and AD pathologies have not been completely elucidated. We report here that Tg2576 mice housed at a high ambient temperature of 30 °C for 13 months showed an increase in the body temperature, which is accompanied by memory impairment and an enhancement of amyloid-β peptides (Aβ) generation through the upregulation of β-site APP cleaving enzyme 1 (BACE1) level and decrease in the level of an Aβ-degrading enzyme, neprilysin (NEP) in the brain, compared with those of Tg2576 mice at 23 °C. High body temperature also increased the levels of heat shock proteins (HSPs), stress-stimulated kinases such as JNK, and total tau, leading to the enhancement of tau phosphorylation at 30 °C. Taken together, our findings suggest that high body temperature exacerbates cognitive function and AD pathologies, which provides a mechanistic insight for its prevention.

Figure 1

High-ambient-temperature exposure increases core body temperature. (a, b) Core body temperature and physical activity of Tg2576 mice housed at 23 °C or 30 °C were analyzed every month from 11 to 15 months using a VitalView system. Average core body temperature (a) and physical activity (b) of mice in light and dark phases at ambient temperatures of 23 °C and 30 °C (n = 7 for each group). (c, d) Circadian rhythm of average core body temperature (c) and physical activity (d) at 15 months of age (n = 7 for each group). Data are expressed as mean ± SD. Significant differences among groups were assessed by repeated measures ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001 vs 23 °C.

Figure 2

High-ambient-temperature exposure induces spatial memory impairment. Memory of Tg2576 mice housed at 23 °C or 30 °C were analyzed using the radial arm maze task at 16 months of age. Mean numbers of working memory errors (a) and reference memory errors (b) in the radial arm maze task (n = 6 for 23 °C, n = 8 for 30 °C). Data are expressed as mean ± SD. Significant differences among groups were assessed by repeated measures ANOVA.

Figure 3

High-ambient-temperature exposure increases Aβ deposition and Aβ levels in the brain cortex via the upregulation of BACE1. After the physiological analyses, brain samples of 17-month-old Tg2576 mice housed at 23 °C or 30 °C were used for Aβ staining, sandwich ELISA, and Western immunoblotting. (a) Sagittal brain sections of mice were stained with the anti-Aβ antibody (82E1) recognizing both Aβ40 and Aβ42 to detect Aβ deposition. Representative images are shown on the left panel. Aβ deposits in the cortex and hippocampus were quantified as the percentage of the immunostained area with respect to the total area examined (right panel). (b) Soluble and insoluble Aβ40 and Aβ42 levels in the brain cortex were measured by sandwich ELISA. Aβ levels were normalized to brain tissue weight. (c) Protein levels of APP, ADAM10, BACE1, PS1, sAPPβ, CTFβ, and α-tubulin in the brain cortex were determined by Western immunoblotting. Representative immunoblots and relative protein levels quantified by densitometry are shown in the left and right panels, respectively. The data are expressed as mean ± SD, n = 6 for 23 °C, n = 6 for 30 °C, *p < 0.05, **p < 0.01, ***p < 0.001 vs 23 °C, n.s., no significant difference, as determined by Student’s t-test. Scale bars: 500 μm.

Figure 4

High-ambient-temperature exposure increases IDE level and decreases NEP level in the brain cortex. Protein levels of ABCA1, ApoE, IDE, NEP and α-tubulin in the brain cortex of 17-month-old mice housed at 23 °C or 30 °C were determined by Western immunoblotting. Representative immunoblots and relative protein levels quantified by densitometry are shown in the left and right panels, respectively. The data are expressed as mean ± SD, n = 6 for 23 °C, n = 6 for 30 °C, **p < 0.01, ***p < 0.001 vs 23 °C, n.s., no significant difference, as determined by Student’s t-test.

Figure 5

High-ambient-temperature exposure increases the levels of total tau, heat shock proteins, and total protein kinases in the cortex. Western immunoblotting was performed using the brain cortex of 17-month-old mice. (a) Protein levels of total- (t-) and phosphorylated- (p-) tau on multiple sites (Ser199, Thr212/Ser214, Ser404, and Ser422), and α-tubulin. (b) Protein levels of HSP90, HSP70, HSP60, and HSP27, and α-tubulin. (c) Protein levels of total (t-) and phosphorylated-(p-) GSK3β, JNK, ERK, and p38. Representative immunoblots and relative protein levels quantified by densitometry are shown in the left and right panels, respectively. The data are expressed as mean ± SD, n = 6 for 23 °C, n = 7 for 30 °C, *p < 0.05, **p < 0.01, ***p < 0.001 vs 23 °C, n.s., no significant difference, as determined by Student’s t-test.

Figure 6

Proposed mechanisms of a sustained high body temperature-induced cognitive impairment. Sustained increase in body temperature increases BACE1 level through JNK activation and decreases NEP level, which exacerbates Aβ pathology. In addition, the sustained increase in body temperature activates stress-activated kinases and increases heat shock proteins leading to tau stabilization, which contribute to tau hyperphosphorylation.