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APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction.

Soto I, Graham LC, Richter HJ, Simeone SN, Radell JE, Grabowska W, Funkhouser WK, Howell MC, Howell GR - PLoS Biol. (2015)

Bottom Line: Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction.Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise.To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus

Exercise improves behavior and neuroplasticity in aged mice.(A) Experimental strategy for voluntary running experiments (Sd = sedentary, Rn = Runner, Sac = sacrifice). (B) Representative image of a mouse running in an electronic wheel and quantification of running distance/night for young and aged mice after 6 months showing no differences between groups. (C) Significant deficits in grip strength found in aged sedentary mice were prevented by voluntary running. (D) Representative images of nests scored 3 and 5 are shown. Nest construction behavior was preserved in aged running mice but not in aged sedentary mice. (E) No statistically significant changes were found in burrowing behavior, however mice in the aging group (3/7) and in the aged sedentary group (2/6) did not engage in this activity, while all young and runner aged mice were able to perform it. (F) Arc (purple) in situ hybridization in aged sedentary and aged runner mice after 2 h of burrowing test. Low levels of Arc expression are found in the cortex of a mouse that did not do the burrowing test. (G) The fraction of NeuN+Arc+ neurons is significantly higher in the aged runners when compared with aged sedentary mice. No changes in the number of cortical NeuN+ neurons between aged sedentary and running mice. In panels B–E and G, values are mean + SEM, n = 7 per group in B–E, and n = 5 per group in G. In (C) **p = 0.0012 ***p = 0.0006, in (D) *p = 0.0165 and 0.0217 respectively, and in (G) *p = 0.0282 by ANOVA followed by Tukey’s posthoc tests. Scale Bar: 50 μm. The data used to make this figure can be found in S1 Dataset.
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pbio.1002279.g005: Exercise improves behavior and neuroplasticity in aged mice.(A) Experimental strategy for voluntary running experiments (Sd = sedentary, Rn = Runner, Sac = sacrifice). (B) Representative image of a mouse running in an electronic wheel and quantification of running distance/night for young and aged mice after 6 months showing no differences between groups. (C) Significant deficits in grip strength found in aged sedentary mice were prevented by voluntary running. (D) Representative images of nests scored 3 and 5 are shown. Nest construction behavior was preserved in aged running mice but not in aged sedentary mice. (E) No statistically significant changes were found in burrowing behavior, however mice in the aging group (3/7) and in the aged sedentary group (2/6) did not engage in this activity, while all young and runner aged mice were able to perform it. (F) Arc (purple) in situ hybridization in aged sedentary and aged runner mice after 2 h of burrowing test. Low levels of Arc expression are found in the cortex of a mouse that did not do the burrowing test. (G) The fraction of NeuN+Arc+ neurons is significantly higher in the aged runners when compared with aged sedentary mice. No changes in the number of cortical NeuN+ neurons between aged sedentary and running mice. In panels B–E and G, values are mean + SEM, n = 7 per group in B–E, and n = 5 per group in G. In (C) **p = 0.0012 ***p = 0.0006, in (D) *p = 0.0165 and 0.0217 respectively, and in (G) *p = 0.0282 by ANOVA followed by Tukey’s posthoc tests. Scale Bar: 50 μm. The data used to make this figure can be found in S1 Dataset.

Mentions: Aging is generally accompanied by cognitive decline and sensorimotor deficits that affect the performance of ADL in the aged population [4,5]. Lifestyle choices such as exercise have been shown to have beneficial effects on the aging brain [9,13], including increased brain volume [4,11], improved performance in several cognitive and motor tasks [4], and neuronal function [9]. Also, a recent study claimed a third of AD cases could be attributed in part to physical inactivity [23]. However, the impact of long-term physical exercise on the health of the neurovascular unit has not been determined. To assess this, mice were provided access to a running wheel from 12 months old (equivalent to middle aged in humans) and assessed at 18 months of age (equivalent to early old age [~60 y old] in humans where risk of AD is greatly increased) (Fig 5A). Voluntary running was preferred to exercise by forced treadmill to remove any potential confounding effects of stress [24]. In addition, voluntary running in mice can induce adaptive physiological changes in cardiac and skeletal muscle showing it is a good method to assess biological changes as a result of exercise [25]. No differences in average running distance (~2 miles/night/mouse) between the young (7 mo) and aged (18 mo) groups of mice were found after 6 months with the running wheel (Fig 5B), indicating that aged mice were able to maintain their running capacity during the 6 months period. Exercised aged mice were first assessed for overall improvement in behavior and neuronal activity. Physical activity improves ADL in humans, and so common daily behaviors in mice—grip strength, nesting, and burrowing—were assessed in exercised and nonexercised (sedentary) mice (Fig 5C–5E). Significant improvements in both grip strength (Fig 5C) and nesting behavior (Fig 5D) were observed in running aged mice (18 mo) compared to sedentary aged mice (18 mo) and were similar to levels seen in aging (12 mo) mice. Burrowing also appeared to be improved but was not statistically significant (Fig 5E). These results indicate that physical activity improved the capabilities and motivation of old mice to engage and perform typical spontaneous behaviors that seem to be affected by aging.


APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction.

Soto I, Graham LC, Richter HJ, Simeone SN, Radell JE, Grabowska W, Funkhouser WK, Howell MC, Howell GR - PLoS Biol. (2015)

Exercise improves behavior and neuroplasticity in aged mice.(A) Experimental strategy for voluntary running experiments (Sd = sedentary, Rn = Runner, Sac = sacrifice). (B) Representative image of a mouse running in an electronic wheel and quantification of running distance/night for young and aged mice after 6 months showing no differences between groups. (C) Significant deficits in grip strength found in aged sedentary mice were prevented by voluntary running. (D) Representative images of nests scored 3 and 5 are shown. Nest construction behavior was preserved in aged running mice but not in aged sedentary mice. (E) No statistically significant changes were found in burrowing behavior, however mice in the aging group (3/7) and in the aged sedentary group (2/6) did not engage in this activity, while all young and runner aged mice were able to perform it. (F) Arc (purple) in situ hybridization in aged sedentary and aged runner mice after 2 h of burrowing test. Low levels of Arc expression are found in the cortex of a mouse that did not do the burrowing test. (G) The fraction of NeuN+Arc+ neurons is significantly higher in the aged runners when compared with aged sedentary mice. No changes in the number of cortical NeuN+ neurons between aged sedentary and running mice. In panels B–E and G, values are mean + SEM, n = 7 per group in B–E, and n = 5 per group in G. In (C) **p = 0.0012 ***p = 0.0006, in (D) *p = 0.0165 and 0.0217 respectively, and in (G) *p = 0.0282 by ANOVA followed by Tukey’s posthoc tests. Scale Bar: 50 μm. The data used to make this figure can be found in S1 Dataset.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4626092&req=5

pbio.1002279.g005: Exercise improves behavior and neuroplasticity in aged mice.(A) Experimental strategy for voluntary running experiments (Sd = sedentary, Rn = Runner, Sac = sacrifice). (B) Representative image of a mouse running in an electronic wheel and quantification of running distance/night for young and aged mice after 6 months showing no differences between groups. (C) Significant deficits in grip strength found in aged sedentary mice were prevented by voluntary running. (D) Representative images of nests scored 3 and 5 are shown. Nest construction behavior was preserved in aged running mice but not in aged sedentary mice. (E) No statistically significant changes were found in burrowing behavior, however mice in the aging group (3/7) and in the aged sedentary group (2/6) did not engage in this activity, while all young and runner aged mice were able to perform it. (F) Arc (purple) in situ hybridization in aged sedentary and aged runner mice after 2 h of burrowing test. Low levels of Arc expression are found in the cortex of a mouse that did not do the burrowing test. (G) The fraction of NeuN+Arc+ neurons is significantly higher in the aged runners when compared with aged sedentary mice. No changes in the number of cortical NeuN+ neurons between aged sedentary and running mice. In panels B–E and G, values are mean + SEM, n = 7 per group in B–E, and n = 5 per group in G. In (C) **p = 0.0012 ***p = 0.0006, in (D) *p = 0.0165 and 0.0217 respectively, and in (G) *p = 0.0282 by ANOVA followed by Tukey’s posthoc tests. Scale Bar: 50 μm. The data used to make this figure can be found in S1 Dataset.
Mentions: Aging is generally accompanied by cognitive decline and sensorimotor deficits that affect the performance of ADL in the aged population [4,5]. Lifestyle choices such as exercise have been shown to have beneficial effects on the aging brain [9,13], including increased brain volume [4,11], improved performance in several cognitive and motor tasks [4], and neuronal function [9]. Also, a recent study claimed a third of AD cases could be attributed in part to physical inactivity [23]. However, the impact of long-term physical exercise on the health of the neurovascular unit has not been determined. To assess this, mice were provided access to a running wheel from 12 months old (equivalent to middle aged in humans) and assessed at 18 months of age (equivalent to early old age [~60 y old] in humans where risk of AD is greatly increased) (Fig 5A). Voluntary running was preferred to exercise by forced treadmill to remove any potential confounding effects of stress [24]. In addition, voluntary running in mice can induce adaptive physiological changes in cardiac and skeletal muscle showing it is a good method to assess biological changes as a result of exercise [25]. No differences in average running distance (~2 miles/night/mouse) between the young (7 mo) and aged (18 mo) groups of mice were found after 6 months with the running wheel (Fig 5B), indicating that aged mice were able to maintain their running capacity during the 6 months period. Exercised aged mice were first assessed for overall improvement in behavior and neuronal activity. Physical activity improves ADL in humans, and so common daily behaviors in mice—grip strength, nesting, and burrowing—were assessed in exercised and nonexercised (sedentary) mice (Fig 5C–5E). Significant improvements in both grip strength (Fig 5C) and nesting behavior (Fig 5D) were observed in running aged mice (18 mo) compared to sedentary aged mice (18 mo) and were similar to levels seen in aging (12 mo) mice. Burrowing also appeared to be improved but was not statistically significant (Fig 5E). These results indicate that physical activity improved the capabilities and motivation of old mice to engage and perform typical spontaneous behaviors that seem to be affected by aging.

Bottom Line: Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction.Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise.To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus