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. 2022 Sep 30;14(1):143.
doi: 10.1186/s13195-022-01085-6.

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise

Jogender Mehla  1   2 , Scott H Deibel  1   3 , Hadil Karem  1 , Shakhawat Hossain  1 , Sean G Lacoursiere  1 , Robert J Sutherland  1 , Majid H Mohajerani #  4 , Robert J McDonald #  5
Affiliations

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise

Jogender Mehla et al. Alzheimers Res Ther. .

Abstract

Background: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise.

Methods: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells.

Results: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise.

Conclusion: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.

Keywords: APPNL-G-F mice; Alzheimer disease; Choline acetyltransferase; Cognitive dysfunction; Microgliosis; Physical exercise.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart for a detail experimental plan and groups for the current study
Fig. 2
Fig. 2
Representative pool schematic showing the size of the outer region of pool and the inner region. Any swimming in the thigmotaxis region (blue) was counted as time in thigmotaxis. Adopted from the ReadMe in the wtr2100 documentation
Fig. 3
Fig. 3
Effects of long-term voluntary exercise on spatial learning and memory functions of 12-month-old APPNL-G-F mice in the MWT. A Mean latency to find the hidden escape platform during the acquisition phase. B Mean swim speed during the acquisition phase. C Percent thigmotaxis shown by mice on each day during the acquisition phase. D Percent thigmotaxis shown by mice during the acquisition phase (average of days 1–8). E Percent time spent by mice in target quadrant and average of other quadrants during the probe trial. F Average proximity to platform during probe trial. Data is presented as mean±SEM. *p < 0.05, **p < 0.01, ***p < 0.001 are considered as statistically significant. a, as compared to control group; b, as compared to APP-NE group. Control group, C57BL/6 (n= 10). APP-NE group, APPNL-G-F with no exercise (n = 10). APP-Ex group- APPNL-G-F mice exposed to exercise (n = 15)
Fig. 4
Fig. 4
Effect of long-term voluntary exercise on learning and memory functions of 12-month-old APPNL-G-F mice in the novel object recognition (NOR) and fear conditioning tests. A Exploration time on the training day. B Exploration time on the testing day. C Investigation ratio for familiar and novel object. D Percent freezing for tone and contextual fear test. Data is presented as mean±SEM. **p < 0.01, ***p < 0.001; a, as compared with the control group. b, as compared with the APP-NE group. $$p < 0.01, $$$p < 0.001 as compared to familiar object. Control group, C57BL/6 (n = 10). APP-NE group, APPNL-G-F with no exercise (n = 10). APP-Ex group, APPNL-G-F mice exposed to exercise (n = 15)
Fig. 5
Fig. 5
Amyloid plaque distribution in brain of 12-month-old APPNL-G-F mice. A Photomicrographs of amyloid plaques stained with methoxy-XO4 (green) in the brain. B, C Corresponding distributions of plaque size by total number of plaques. D Percent amyloid plaque area in brain. E Total amyloid plaques number in the brain. Scale bars represent 1 mm for atlas section +1.94 mm and 2.5 mm for atlas section −3.08 mm. Data is presented as mean ± SEM. *p < 0.05—as compared to the APP-NE group. APP-NE group, APPNL-G-F with no exercise (n = 4). APP-Ex group, APPNL-G-F mice exposed to exercise (n = 4)
Fig. 6
Fig. 6
Amyloid plaque distribution in different brain regions of 12-month-old APPNL-G-F mice. A Amyloid plaque area in medial prefrontal cortex (mPFC). B Amyloid plaque area in hippocampus (HPC). C Amyloid plaque area in retrospenial area (RSA). D Amyloid plaque area in perirhinal cortex (PRhC). E Amyloid plaque area in cortical amygdalar area (CAA). Data is presented as mean±SEM. *p < 0.05, **p < 0.01, as compared to the APP-NE group. APP-NE group, APPNL-G-F with no exercise (n = 4). APP-Ex group, APPNL-G-F mice exposed to exercise (n = 4)
Fig. 7
Fig. 7
Microgliosis in brain of 12 months old mice. A Photomicrographs of activated IBA-1, a marker of microgliosis in brain. B Activated IBA-1 immunostained area in brain atlas section +1.94 mm and atlas section −3.08 mm. C Activated IBA-1 number in brain atlas sections +1.94 mm and atlas section -3.08 mm. Scale bars represent 1 mm for atlas section +1.94 mm and 2.5 mm for atlas section −3.08 mm. Data is presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p<0.001; a, as compared to the control group; b, as compared to the APP-NE group. Control group, C57BL/6 (n = 5). APP-NE group, APPNL-G-F with no exercise (n = 4). APP-Ex group, APPNL-G-F mice exposed to exercise (n = 4)
Fig. 8
Fig. 8
Microgliosis in different brain regions of 12-month-old mice. A Activated IBA-1 immunostained area in medial prefrontal cortex (mPFC). B Activated IBA-1 immunostained area in hippocampus (HPC). C Activated IBA-1 immunostained area in retrospenial area (RSA). D Activated IBA-1 immunostained area in perirhinal cortex (PRhC). E Activated IBA-1 immunostained area in cortical amygdalar area (CAA). Data is presented as mean ± SEM. *p < 0.05, **p < 0.01; a, as compared to the control group; b, as compared to the APP-NE group. Control group, C57BL/6 (n = 5). APP-NE group, APPNL-G-F with no exercise (n= 4). APP-Ex group, APPNL-G-F mice exposed to Exercise (n = 4)
Fig. 9
Fig. 9
Amyloid pathology, microgliosis, and ChAT+ cells in the medial septum-diagonal band (MSDB) complex of the basal forebrain of 12-month-old mice. A Photomicrographs of amyloid plaques stained with methoxy-XO4 (green) in MSDB complex. B Photomicrographs of immunostaining of activated IBA-1 (red) in MSDB complex. C Photomicrographs of immunohistochemistry staining of choline acetyl transferase (ChAT) in MSDB complex. ChAT, a cholinergic marker stained with monoclonal rabbit anti-ChAT antibody (red); DAPI, stained the nuclei (blue). Scale bar, 500 μm for whole sections. D Corresponding distributions of plaque size by total number of plaques. E Total amyloid plaques number in MSDB complex. F Percent amyloid plaque area in MSDB complex. G Activated IBA-1 number in MSDB complex. H Activated IBA-1 percent area in MSDB complex. I Quantification of ChAT in MSDB complex. Data is presented as mean±SEM. *p < 0.05, **p < 0.01, ***p < 0.001 are considered as statistically significant. $, as compared to APP-NE group; b, as compared to control group; c, as compared to APP-NE group. Control group, C57BL/6 (n = 5). APP-NE group, APPNL-G-F with no exercise (n = 4). APP-Ex group, APPNL-G-F mice exposed to exercise (n = 4)
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