Alexander disease: an astrocytopathy that produces a leukodystrophy

Abstract

Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in the CNS do not express GFAP, AxD is a primary astrocyte disease. Astrocytes acquire a large number of pathological features, including changes in morphology, the loss or diminution of a number of critical astrocyte functions and the activation of cell stress and inflammatory pathways. AxD is also characterized by white matter degeneration, a pathology that has led it to be included in the "leukodystrophies." Furthermore, variable degrees of neuronal loss take place. Thus, the astrocyte pathology triggers alterations in other cell types. Here, we will review the neuropathology of AxD and discuss how a disease of astrocytes can lead to severe pathologies in non-astrocytic cells. Our knowledge of the pathophysiology of AxD will also lead to a better understanding of how astrocytes interact with other CNS cells and how astrocytes in the gliosis that accompanies many neurological disorders can damage the function and survival of other cells.

Keywords: Alexander disease; GFAP; astrocytes; leukodystrophy.

Figure 1

Hemispheric white matter from a patient with Type I AxD. A. The white matter contains innumerous RFs (bright red profiles, arrows). There is a generally pale background, reflecting myelin loss. B. RFs inside astrocyte cell bodies (two marked with arrows) in this AxD individual. C. A multinucleated astrocyte. D. An astrocyte with a mitotic figure. This cell resembles the “Creutzfeldt” astrocyte – mitotic figures in reactive astrocytes, described in inflammatory diseases such as multiple sclerosis. E. Deep cerebellar white matter from this patient. There are many RFs (arrows) and many enlarged astrocytes (astrocyte nuclei are large and round to oval). All Figures H&E. Scale Bars (A, E) 200 μm, (B) 100 μm, (C) 50 μm, (D) 50 μm.

Figure 2

Temporal white matter from a patient with Type II AxD. A. The periventricular white matter is pale and contains RFs (arrows) and enlarged astrocytes. B. The deep white matter shows scattered RFs (arrows), but the degree of myelination appears normal. C. The astrocytes and the degree of myelination in U fibers appears normal. All Figures H&E. Scale Bars (A, B, C) 200 μm.

Figure 3

Isocortex of a Type I AxD patient. A. Isocortex does not show RFs, although some astrocytes are enlarged (arrows). B. RFs (2 marked by arrows) accumulate at the pial surface (top of image) in the endfeet of astrocytes. All Figures H&E. Scale Bars (A) 50 μm, (B) 150 μm.

Figure 4

A. Inferior olive of a Type I AxD patient. There are many RFs (arrows) interspersed among olivary neurons, which themselves appear morphologically unremarkable. B. Pons of a Type I AxD patient showing a perivascular lymphocytic infiltrate. Many of the surrounding astrocytes contain RFs. All Figures H&E. Scale Bars (A) 100 μm, (B) 50 μm.

Figure 5

Oligodendrocyte changes in AxD mice. A–C. Bulbous‐like enlargements of myelin in TG mice identified with MBP and PLP (A, enlarged boxed areas shown in A1 and A2) and with CNP (B, C, arrows) immunostaining. A, B – hippocampus; C – isocortex. D. Death‐related changes in TG/KI mouse oligodendrocytes. Cleaved caspase 3 (caspase 3) immunopositive oligodendrocytes are indicated with boxed area and arrow in D. D1 – enlarged boxed area in (D). Note shrunken nucleus of caspase3 immunopositive oligodendrocyte in D1″. Confocal microscopy. Scale bars: 45 μm in (A, C); 15 μm in (B); 85 µm in (D).

Figure 6

Aberrant forms of astrocytes with thick, short, “truncated” processes in AxD mice. A. An astrocyte with abnormal processes (arrow in A′) is located near an astrocyte with longer, more branched processes, A, B. These abnormal astrocytes show the presence of CD44. A″, B′. Abnormal astrocytes contain many RFs (arrows in A″, B1′). RFs are delineated with DAPI stain, as shown in 51. Confocal microscopy. Scale bars: 55 μm.

Figure 7

Degenerative features of astrocytes in TG AxD mice. A. Death of astrocyte with shrunken nucleus. RFs are marked with arrows in A1″. B. Activated microglial cells (Iba1+) encircle astrocyte (GFAP+). RFs are marked with arrows in B1″. Confocal microscopy. (C, D) “Dark” forms of astrocytes filled with RFs (arrows, indicating some RFs). Electron microscopy. N‐nucleus. Scale bars; 50 µm in (A, B); 3 μm in (C, D).