Astrocytes in aged nonhuman primate brain gray matter synthesize excess hyaluronan

Abstract

The glycosaminoglycan hyaluronan (HA) accumulates in central nervous system lesions where it limits astrogliosis but also inhibits oligodendrocyte progenitor cell (OPC) maturation. The role of hyaluronan in normative brain aging has not been previously investigated. Here, we tested the hypothesis that HA accumulates in the aging non-human primate brain. We found that HA levels significantly increase with age in the gray matter of rhesus macaques. HA accumulation was linked to age-related increases in the transcription of HA Synthase-1 (HAS1) expressed by reactive astrocytes but not changes in the expression of other HAS genes or hyaluronidases. HA accumulation was accompanied by increased expression of CD44, a transmembrane HA receptor. Areas of gray matter with elevated HA in older animals demonstrated increased numbers of olig2+ OPCs, consistent with the notion that HA may influence OPC expansion or maturation. Collectively, these data indicate that HAS1 and CD44 are transcriptionally upregulated in astrocytes during normative aging and are linked to HA accumulation in gray matter.

Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline

“…A variety of conditions that reduce cerebral blood flow, including reduced angiogenesis, tortuous arterioles, and hypoxia-induced loss of capillaries, may each result in WM damage in the elderly (Fernando et al 2004;Brown and Thore 2011). The finding that myelin-and axon-associated free radical injury, as assessed by measurements of distinct isoprostanes, inversely correlated with FA in vascular brain injury independent of AD (Back et al 2011) support a model whereby vascular changes cause age-related WM damage through oxidative stress. Fig.…”

“…A similar result showed that normal aged and mildly cognitively impaired (MCI) subjects differed from AD, in that the latter had a differential decrease of FA in the left anterior temporal lobe, consistent with disease progression (Damoiseaux et al 2009). Interestingly, lower FA was associated significantly with coincident AD and vascular brain injury (Back et al 2011). Given that AD and vascular brain injury are commonly co-morbid (Sonnen et al 2009), it is possible that earlier findings of lower FA in AD patients reflected vascular disturbances as opposed to a specific effect of AD pathology.…”

“…Both Notch signaling and bone morphogenetic proteins induced during reactive astrogliosis have been implicated in blocking OPC differentiation and remyelination (e.g., John et al 2002;Wang et al 2011). Astrogliosis is a reliable marker of mammalian brain aging in both GM and WM (Brizzee et al 1968;Sturrock 1980;Hughes and Lantos 1987;Sloane et al 2000;Cargill et al 2011). Thus, the signals associated with astrogliosis may promote remyelination failure during normative aging.…”

“…One study utilizing electrophoretic separation of glycosaminoglycans indicated a moderate increase in HA concentration in 30 month-old rat brain tissue compared to tissues from younger animals (Jenkins and Bachelard 1988a). HA is similarly elevated in brains from patients with Alzheimer's disease (Suzuki et al, 1965;Jenkins and Bachelard 1988b;Back et al 2011) and in aged individuals with vascular brain injury (Back et al 2011). We recently found that both HA and CD44 are elevated during normative aging in the prefrontal cortex of rhesus and Japanese macaques (Cargill et al 2011).…”

“…HA is similarly elevated in brains from patients with Alzheimer's disease (Suzuki et al, 1965;Jenkins and Bachelard 1988b;Back et al 2011) and in aged individuals with vascular brain injury (Back et al 2011). We recently found that both HA and CD44 are elevated during normative aging in the prefrontal cortex of rhesus and Japanese macaques (Cargill et al 2011). The most significant increases in HA occurred in the GM, although there was a trend towards increased HA in WM in oldest-old animals.…”