Filamentous tau in oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation

Abstract

We recently reported a transgenic mouse line (JNPL3) that expresses mutant (P301L) tau and develops neurofibrillary tangles composed of filamentous tau aggregates. Here we show that these mice have abnormal tau filaments not only in neurons, but also in oligodendrocytes and astrocytes. Similar results were detected in another transgenic line (JNPL2+3+) that expresses the longest human tau isoform with the P301L mutation. The ultrastructure of the tau filaments and immunoreactivity with tau and ubiquitin antibodies were similar in glia and neurons. Given similarities of the lesions in the mice to human neuronal and glial inclusions, these transgenic mice appear to be a valuable model to study pathogenesis of the neurodegenerative tauopathies.

Figure 1.

A: Three cells in the posterior horn are shown, with the largest cell being a neuron with a prominent nucleus (Nu), and lipofuscin granules (Lp). Note in-foldings of the nuclear membrane (short arrows). The middle cell is an oligodendrocyte (Olg) with clumped chromatin along the nuclear periphery and a prominent perinuclear cis-tern. Note the filamentous cytoplasmic inclusion (long arrow). The third cell may be a protoplasmic astrocyte of possibly a glial progenitor cell. B: Higher magnification of the filamentous inclusion in A shows straight and wavy filaments (arrows) with a diameter of 15 to 20 nm. Note the clear spaces between filaments. Scale bars, 0.2 μm.

Figure 2.

A: An oligodendrocyte and several myelinated axons (Ax). B: Boxed area in A showing immunogold labeling of filaments by a human-specific tau antibody, E1 (short arrows). Note the close proximity of filaments to the nuclear membrane (long arrows). Scale bars: 1 μm (A); 0.2 μm (B).

Figure 3.

A: A satellite oligodendrocyte next to a neuron (Nu). B: Boxed area in A showing filaments labeled by ubiquitin antibody (arrows). A cluster of filaments abuts the nuclear membrane (open arrow). Scale bars: 1 μm (A); 0.2 μm (B).

Figure 4.

a: Tau immunostain shows immunoreactivity of the cytoplasm of a subpial astrocyte. b: Oligodendroglia in spinal white matter have filamentous lesions that coil around the nucleus. c and d: Oligodendroglial inclusions in transgenic mice are argyrophilic with Gallyas silver stain similar to coiled bodies in human tauopathies.

Figure 5.

A: A subpial astrocyte in white matter of the spinal cord. B: Boxed area of the cell process in A showing tau filaments that are labeled with immunogold and a human-specific antibody, E1 (arrows). The astrocytic nature of the cell is confirmed by the presence of bundles of characteristic glial fibrils (asterisks). Note the close association of these two types of filaments. Scale bars: 1 μm (A); 0.125 μm (B).