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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

Microglia/monocyte density is increased in regions with pericyte loss in the aged cortex.(A) Representative images showing extravascular deposition of FIBRIN (red) surrounded by microglia with increased LECTIN immunoreactivity (light blue). (B–C) A significant increase in IBA1+ microglia/monocyte cells (green) in the aged cortex coincides with the significant decrease of PDGFRβ+ pericytes (magenta) in the same region when compared with the cortex from young mice. (D) In the aged cortex, electron micrographs show active phagocytic microglia/monocytes (M) in close proximity to apoptotic cell bodies (AC) in close contiguity to a blood vessel (BV), to a degenerated pericyte (DP), and to a blood vessel with high transcytosis activity. Damaged axons (blue arrows) and vesicular bodies with cellular debris (magenta arrows) are also observed in these regions. In (C) values are relative mean + SEM to the young values, n = 4 mice per group, **p < 0.005 by unpaired t test. Scale Bars: 50 μm (A–B) and 2 μm (D). The data used to make this figure can be found in S1 Dataset.
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pbio.1002279.g003: Microglia/monocyte density is increased in regions with pericyte loss in the aged cortex.(A) Representative images showing extravascular deposition of FIBRIN (red) surrounded by microglia with increased LECTIN immunoreactivity (light blue). (B–C) A significant increase in IBA1+ microglia/monocyte cells (green) in the aged cortex coincides with the significant decrease of PDGFRβ+ pericytes (magenta) in the same region when compared with the cortex from young mice. (D) In the aged cortex, electron micrographs show active phagocytic microglia/monocytes (M) in close proximity to apoptotic cell bodies (AC) in close contiguity to a blood vessel (BV), to a degenerated pericyte (DP), and to a blood vessel with high transcytosis activity. Damaged axons (blue arrows) and vesicular bodies with cellular debris (magenta arrows) are also observed in these regions. In (C) values are relative mean + SEM to the young values, n = 4 mice per group, **p < 0.005 by unpaired t test. Scale Bars: 50 μm (A–B) and 2 μm (D). The data used to make this figure can be found in S1 Dataset.

Mentions: Although transcriptional profiling data in the HP did not show pathways relevant to neurovascular unit dysfunction as being differentially affected by age (S4 Table), genes relevant to the neurovascular unit, including Pdgfrβ (−1.36) and Cldn5 (−1.63) were down-regulated (S2 Table), suggesting possible dysfunction to the neurovascular unit in the HP also. Therefore, we assessed neurovascular health in the CA1 region of the HP. Similar to our findings in the FPC, COL4+ microvessels and coverage of PDGFRβ+ were also significantly reduced in the hippocampal CA1 region of aged mice when compared with young (S3 Fig). Furthermore, ultrastructural analysis identified several degenerating pericytes in the cortex of aged mice that were not observed in young mice (Fig 2D). Pericytes are critical components of the neurovascular unit and play a key role in the regulation of BM, vessel contractility, and inhibition of vesicular transcytosis through endothelial cells [19]. Increased endothelial vesicular transcytosis was frequently observed in the aged cortex (Fig 2E), further supporting age-related pericyte dysfunction or loss. Fibrin deposition and pericyte loss were associated with an increase in the number of activated microglia/monocytes (Fig 3A and 3B). Ultrastructural analyses suggested that these microglia/monocytes were phagocytic when in close proximity to areas of pericyte degeneration and increased endothelial transcytosis activity (Fig 3C).


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)

Microglia/monocyte density is increased in regions with pericyte loss in the aged cortex.(A) Representative images showing extravascular deposition of FIBRIN (red) surrounded by microglia with increased LECTIN immunoreactivity (light blue). (B–C) A significant increase in IBA1+ microglia/monocyte cells (green) in the aged cortex coincides with the significant decrease of PDGFRβ+ pericytes (magenta) in the same region when compared with the cortex from young mice. (D) In the aged cortex, electron micrographs show active phagocytic microglia/monocytes (M) in close proximity to apoptotic cell bodies (AC) in close contiguity to a blood vessel (BV), to a degenerated pericyte (DP), and to a blood vessel with high transcytosis activity. Damaged axons (blue arrows) and vesicular bodies with cellular debris (magenta arrows) are also observed in these regions. In (C) values are relative mean + SEM to the young values, n = 4 mice per group, **p < 0.005 by unpaired t test. Scale Bars: 50 μm (A–B) and 2 μm (D). The data used to make this figure can be found in S1 Dataset.
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Related In: Results  -  Collection

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

pbio.1002279.g003: Microglia/monocyte density is increased in regions with pericyte loss in the aged cortex.(A) Representative images showing extravascular deposition of FIBRIN (red) surrounded by microglia with increased LECTIN immunoreactivity (light blue). (B–C) A significant increase in IBA1+ microglia/monocyte cells (green) in the aged cortex coincides with the significant decrease of PDGFRβ+ pericytes (magenta) in the same region when compared with the cortex from young mice. (D) In the aged cortex, electron micrographs show active phagocytic microglia/monocytes (M) in close proximity to apoptotic cell bodies (AC) in close contiguity to a blood vessel (BV), to a degenerated pericyte (DP), and to a blood vessel with high transcytosis activity. Damaged axons (blue arrows) and vesicular bodies with cellular debris (magenta arrows) are also observed in these regions. In (C) values are relative mean + SEM to the young values, n = 4 mice per group, **p < 0.005 by unpaired t test. Scale Bars: 50 μm (A–B) and 2 μm (D). The data used to make this figure can be found in S1 Dataset.
Mentions: Although transcriptional profiling data in the HP did not show pathways relevant to neurovascular unit dysfunction as being differentially affected by age (S4 Table), genes relevant to the neurovascular unit, including Pdgfrβ (−1.36) and Cldn5 (−1.63) were down-regulated (S2 Table), suggesting possible dysfunction to the neurovascular unit in the HP also. Therefore, we assessed neurovascular health in the CA1 region of the HP. Similar to our findings in the FPC, COL4+ microvessels and coverage of PDGFRβ+ were also significantly reduced in the hippocampal CA1 region of aged mice when compared with young (S3 Fig). Furthermore, ultrastructural analysis identified several degenerating pericytes in the cortex of aged mice that were not observed in young mice (Fig 2D). Pericytes are critical components of the neurovascular unit and play a key role in the regulation of BM, vessel contractility, and inhibition of vesicular transcytosis through endothelial cells [19]. Increased endothelial vesicular transcytosis was frequently observed in the aged cortex (Fig 2E), further supporting age-related pericyte dysfunction or loss. Fibrin deposition and pericyte loss were associated with an increase in the number of activated microglia/monocytes (Fig 3A and 3B). Ultrastructural analyses suggested that these microglia/monocytes were phagocytic when in close proximity to areas of pericyte degeneration and increased endothelial transcytosis activity (Fig 3C).

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