MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging.

Nagendran Muthusamy,Jill M Weimer,Philip Sannes,Adam J Moeser,Perry J Blackshear,Laura J Sommerville,H Troy Ghashghaei,Deborah J Stumpo,Kenneth Adler

doi:10.1111/acel.12354

Abstract

Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain.

Highlights

Ependymal cells (ECs) form the epithelial lining of the ventricular surfaces in the brain
Antibody staining in cross sections of 2-month-old brains (2M) showed myristoylated alanine-rich protein kinase C substrate (MARCKS) enriched in the proximal aspects of apical cilia in ECs (Figs 1B, S1; Movie S1)
As phosphorylation status of MARCKS is an important regulator of its subcellular localization in various cell types, we examined p-MARCKS distribution in 2M ECs in vivo (Fig. 1B; Movie S2). p-MARCKS, which represents only a fraction of the total MARCKS pool, is distributed throughout the cytosol away from the apical surface of young ECs

Summary

Introduction

Ependymal cells (ECs) form the epithelial lining of the ventricular surfaces in the brain. They are highly polarized with adherens junctions at their. There is noticeable reduction in the density of motile cilia on the apical surface of ECs in the aged brain (Luo et al, 2008; Capilla-Gonzalez et al, 2014). Whether loss of ependymal integrity during aging can induce interstitial defects has yet to be tested Testing this hypothesis requires new models in which ependymal cell functions can be modified to mimic aged ependyma, that is, ones in which ECs are precociously aged

Results

Discussion

Conclusion