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Age-related decline in oligodendrogenesis retards white matter repair in mice.

ABSTRACT: Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month-old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells to sublethal 7-day CoCl2 treatment to induce chemical hypoxic stress.Baseline myelin density in the corpus callosum was similar in 2-month and 8-month-old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in cyclic AMP response element-binding protein signaling may be involved because activating cyclic AMP response element-binding protein with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of oligodendrocyte precursor cells, alleviated myelin loss, and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of oligodendrocyte precursor cells.An age-related decline in cyclic AMP response element-binding protein-mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate cyclic AMP response element-binding protein signaling provide a potential therapeutic approach for treating white matter injury in aging brains.

SUBMITTER: Miyamoto N

PROVIDER: S-EPMC3818687 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Age-related decline in oligodendrogenesis retards white matter repair in mice.

Miyamoto Nobukazu N Pham Loc-Duyen D LD Hayakawa Kazuhide K Matsuzaki Toshinori T Seo Ji Hae JH Magnain Caroline C Ayata Cenk C Kim Kyu-Won KW Boas David D Lo Eng H EH Arai Ken K

Stroke 20130723 9

<h4>Background and purpose</h4>Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.<h4>Methods</h4>A mouse model of prolonged cerebral hypoperfusion was prepa ...[more]

PMID: 23881957

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Project description:BackgroundResearch suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these factors and their relationship to cognitive decline in cognitively unimpaired older adults without subjective cognitive decline.MethodsA total of 230 subjects with cerebrospinal fluid (CSF) Aß42, CSF pTau181, white matter lesions (WMLs) used as a proxy of CSVD, and cognitive scores from the Alzheimer's Disease Neuroimaging Initiative were included. Associations between each factor and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models.ResultsAt baseline, there was an inverse association between WML load and Aß42 (t = -4.20, p <.001). There was no association between WML load and pTau (t = 0.32, p = 0.75), nor with Aß42 and pTau (t = 0.51, p =.61). Correcting for age, sex and education, baseline WML load was associated with baseline ADAS-13 scores (t = 2.59, p =.01) and lower follow-up executive functioning (t = -2.84, p =.005). Baseline Aß42 was associated with executive function at baseline (t = 3.58, p<.004) but not at follow-up (t = 1.05, p = 0.30), nor with ADAS-13 at baseline (t = -0.24, p = 0.81) or follow-up (t = 0.09, p = 0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up.ConclusionBoth baseline Aß42 and WML load are associated with some baseline cognition scores, but only baseline WML load is associated with follow-up executive functioning. This finding suggests that WMLs may be one of the earliest clinical manifestations that contributes to future cognitive decline in cognitively healthy older adults. Given that healthy older adults with WMLs exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMLs.

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Age-related decline in oligodendrogenesis retards white matter repair in mice.

Publications

Age-related decline in oligodendrogenesis retards white matter repair in mice.

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