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Brain regional angiogenic potential at the neurovascular unit during normal aging.

ABSTRACT: Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young versus aged mice by laser capture microdissection coupled to quantitative real-time polymerase chain reaction (PCR). Complementary quantitative capillary density/branching studies were performed as well. Effects of physical exercise were also assayed to determine if age-related trends could be reversed. Additionally, gene response to hypoxia was probed to highlight age-associated weaknesses in adapting to this angiogenic stress. Aging impacted resting expression of angiogenesis-associated genes at the NVU in a region-dependent manner. Physical exercise reversed some of these age-associated gene trends, as well as positively influenced cerebral capillary density/branching in a region-dependent way. Lastly, hypoxia revealed a weaker angiogenic response in aged brain. These results suggest heterogeneous changes in angiogenic capacity of the brain during normal aging, and imply a therapeutic benefit of physical exercise that acts at the level of the NVU.

SUBMITTER: Murugesan N

PROVIDER: S-EPMC3266473 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Brain regional angiogenic potential at the neurovascular unit during normal aging.

Murugesan Nivetha N Demarest Tyler G TG Madri Joseph A JA Pachter Joel S JS

Neurobiology of aging 20111021 5

Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young versus aged mice by laser capture microdissection coupled to quantitative real-time polymerase chain reaction (PCR). Complementary quantitative capillary density/branching studies were performed as well. Effects of ...[more]

PMID: 22019053

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Project description:Background: Neuroscience lacks a reliable method of screening the early stages of dementia. Objective: To improve the diagnostics of age-related cognitive functions by developing insight into the proportionality of age-related changes in cognitive subdomains. Materials and Methods: We composed a battery of psychophysiological tests and collected an open-access psychophysiological outcomes of brain atrophy (POBA) dataset by testing individuals without dementia. To extend the utility of machine learning (ML) classification in cognitive studies, we proposed estimates of the disproportional changes in cognitive functions: an index of simple reaction time to decision-making time (ISD), ISD with the accuracy performance (ISDA), and an index of performance in simple and complex visual-motor reaction with account for accuracy (ISCA). Studying the distribution of the values of the indices over age allowed us to verify whether diverse cognitive functions decline equally throughout life or there is a divergence in age-related cognitive changes. Results: Unsupervised ML clustering shows that the optimal number of homogeneous age groups is four. The sample is segregated into the following age-groups: Adolescents ∈ [0, 20), Young adults ∈ [20, 40), Midlife adults ∈ [40, 60) and Older adults ≥60 year of age. For ISD, ISDA, and ISCA values, only the median of the Adolescents group is different from that of the other three age-groups sharing a similar distribution pattern (p > 0.01). After neurodevelopment and maturation, the indices preserve almost constant values with a slight trend toward functional decline. The reaction to a moving object (RMO) test results (RMO_mean) follow another tendency. The Midlife adults group's median significantly differs from the remaining three age subsamples (p < 0.01). No general trend in age-related changes of this dependent variable is observed. For all the data (ISD, ISDA, ISCA, and RMO_mean), Levene's test reveals no significant changes of the variances in age-groups (p > 0.05). Homoscedasticity also supports our assumption about a linear dependency between the observed features and age. Conclusion: In healthy brain aging, there are proportional age-related changes in the time estimates of information processing speed and inhibitory control in task switching. Future studies should test patients with dementia to determine whether the changes of the aforementioned indicators follow different patterns.

Project description:BackgroundThe monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease.MethodsNeurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls.ResultsUltrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density.ConclusionsThese findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease.

Dataset Information

Brain regional angiogenic potential at the neurovascular unit during normal aging.

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Brain regional angiogenic potential at the neurovascular unit during normal aging.

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