Exercise Alleviates Behavioral Disorders but Shapes Brain Metabolism of APP/PS1 Mice in a Region- and Exercise-Specific Manner

Abstract

Exercise plays a beneficial role in the management of Alzheimer's disease (AD), but its effects on brain metabolism are still far from being understood. Here, we examined behavioral changes of APP/PS1 mice after high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) and analyzed metabolomics profiles in the hippocampus, cortex, and hypothalamus by using nuclear magnetic resonance spectroscopy to explore potential metabolic mechanisms. The results demonstrate that both HIIT and MICT alleviated anxiety/depressive-like behaviors as well as learning and memory impairments of AD mice. Metabolomics analysis reveals that energy metabolism, neurotransmitter metabolism, and membrane metabolism were significantly altered in all three brain regions after both types of exercises. Amino acid metabolism was detected to be affected in the cortex and hypothalamus after HIIT and in the hippocampus and hypothalamus after MICT. However, only HIIT significantly altered astrocyte-neuron metabolism in the hippocampus and hypothalamus of AD mice. Therefore, our study suggests that exercise can shape brain metabolism of AD mice in a region-and exercise-specific manner, indicating that the precise modification of brain metabolism by a specific type of exercise might be a novel perspective for the prevention and treatment of AD.

A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology

“…Brain subregions were divided into 53 medium-sized regions according to a previous report. 40 Higher levels of AT8-positive tau signals were observed in ECT and the agranular insular area (AI) of the isocortex, PIR of the olfactory area and the retrohippocampal region (RHP) of the Hippocampal formation ( Fig. 2B ).…”

“…( B ) Integrated tau signal intensity per regional volume across 53 medium-sized subregions, as defined in a previous report. 40 Integrated tau signal intensity per regional volume was calculated by summing the intensity of tau deposit spots within each anatomical region and normalizing this sum by the total volume of the region (expressed in/mm³). This process was facilitated by the integration of the CCFv3 Allen Brain Atlas 39 annotations and volume metrics through the use of CUBIC-Cloud.…”

A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology

“…Brain subregions were divided into 53 medium-sized regions according to a previous report. 40 Higher levels of AT8-positive tau signals were observed in ECT and the agranular insular area (AI) of the isocortex, PIR of the olfactory area and the retrohippocampal region (RHP) of the Hippocampal formation ( Fig. 2B ).…”

“…( B ) Integrated tau signal intensity per regional volume across 53 medium-sized subregions, as defined in a previous report. 40 Integrated tau signal intensity per regional volume was calculated by summing the intensity of tau deposit spots within each anatomical region and normalizing this sum by the total volume of the region (expressed in/mm³). This process was facilitated by the integration of the CCFv3 Allen Brain Atlas 39 annotations and volume metrics through the use of CUBIC-Cloud.…”

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice

“…Regular physical activity can improve glucose utilization, augment mitochondrial function, and increase cerebral blood flow, thereby optimizing energy production and supporting neuronal survival [81] , [82] , [83] . One of the key mechanisms by which exercise exerts its role in AD is by alleviating or recalibrating the aberrant metabolism associated with the disease [15] , [16] , [84] , [85] . Exercise not only fosters optimal brain metabolism but also generates bioactive molecules that support neuronal survival and function [86] .…”

Histone Methylation, Energy Metabolism, and Alzheimer's Disease

“…Running exercise was reported to inhibit TREM2 shedding and maintain TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism, and morphological plasticity in the hippocampus of AD mice [ 188 ]. Besides, Ying et al [ 189 ] observed that amino acid metabolism was affected in the cortex and hypothalamus after high-intensity interval training in APP/PS1 mice. However, the relationship between lifestyle changes and histone methylation has not yet been clearly reported and needs to be further explored.…”

A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology

“…Brain subregions were divided into 53 medium-sized regions according to a previous report. 40 Higher levels of AT8-positive tau signals were observed in ECT and the agranular insular area (AI) of the isocortex, PIR of the olfactory area and the retrohippocampal region (RHP) of the Hippocampal formation ( Fig. 2B ).…”

“…( B ) Integrated tau signal intensity per regional volume across 53 medium-sized subregions, as defined in a previous report. 40 Integrated tau signal intensity per regional volume was calculated by summing the intensity of tau deposit spots within each anatomical region and normalizing this sum by the total volume of the region (expressed in/mm³). This process was facilitated by the integration of the CCFv3 Allen Brain Atlas 39 annotations and volume metrics through the use of CUBIC-Cloud.…”

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice

“…Regular physical activity can improve glucose utilization, augment mitochondrial function, and increase cerebral blood flow, thereby optimizing energy production and supporting neuronal survival [81] , [82] , [83] . One of the key mechanisms by which exercise exerts its role in AD is by alleviating or recalibrating the aberrant metabolism associated with the disease [15] , [16] , [84] , [85] . Exercise not only fosters optimal brain metabolism but also generates bioactive molecules that support neuronal survival and function [86] .…”

Histone Methylation, Energy Metabolism, and Alzheimer's Disease

“…Running exercise was reported to inhibit TREM2 shedding and maintain TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism, and morphological plasticity in the hippocampus of AD mice [ 188 ]. Besides, Ying et al [ 189 ] observed that amino acid metabolism was affected in the cortex and hypothalamus after high-intensity interval training in APP/PS1 mice. However, the relationship between lifestyle changes and histone methylation has not yet been clearly reported and needs to be further explored.…”

A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology

“…Brain subregions were divided into 53 medium-sized regions according to a previous report. 40 Higher levels of AT8-positive tau signals were observed in ECT and the agranular insular area (AI) of the isocortex, PIR of the olfactory area and the retrohippocampal region (RHP) of the Hippocampal formation ( Fig. 2B ).…”

“…( B ) Integrated tau signal intensity per regional volume across 53 medium-sized subregions, as defined in a previous report. 40 Integrated tau signal intensity per regional volume was calculated by summing the intensity of tau deposit spots within each anatomical region and normalizing this sum by the total volume of the region (expressed in/mm³). This process was facilitated by the integration of the CCFv3 Allen Brain Atlas 39 annotations and volume metrics through the use of CUBIC-Cloud.…”

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice

“…Regular physical activity can improve glucose utilization, augment mitochondrial function, and increase cerebral blood flow, thereby optimizing energy production and supporting neuronal survival [81] , [82] , [83] . One of the key mechanisms by which exercise exerts its role in AD is by alleviating or recalibrating the aberrant metabolism associated with the disease [15] , [16] , [84] , [85] . Exercise not only fosters optimal brain metabolism but also generates bioactive molecules that support neuronal survival and function [86] .…”

Histone Methylation, Energy Metabolism, and Alzheimer's Disease

“…Running exercise was reported to inhibit TREM2 shedding and maintain TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism, and morphological plasticity in the hippocampus of AD mice [ 188 ]. Besides, Ying et al [ 189 ] observed that amino acid metabolism was affected in the cortex and hypothalamus after high-intensity interval training in APP/PS1 mice. However, the relationship between lifestyle changes and histone methylation has not yet been clearly reported and needs to be further explored.…”