Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments

Abstract

Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial "multiple system tauopathy with presenile dementia," which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of beta-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.

Figure 1

Temporal cortex from a familial MSTD patient showing neuronal and glial cells stained with phosphorylation-dependent anti-tau antibodies. Neurons and glial cells in grey matter stained with antibodies AT8 (A), AT180 (D), and PHF1 (G). Antibody 12E8 stains granular deposits in neurons and glial cells in both grey (J) and white matter (K). In white matter AT8 (B and C), AT180 (E and F), and PHF1 (H and I) stain numerous glial cells with cytoplasmic inclusions (C, F, and I). (Magnifications: A, B, D, E, G, and H, ×140; C, F, and I, ×448; J, ×760; and K, ×112.)

Figure 2

Temporal cortex from a familial MSTD patient double-stained with the phosphorylation-dependent anti-tau antibody AT8 and the anti-heparan sulfate antibody 10E4. AT8 staining is shown in blue, and 10E4 staining is shown in brown (Nomarski optics). Note staining of some nerve cells and glial cells with 10E4 and double-labeling of nerve cells and glial cells with both AT8 and 10E4. (Bar = 23.5 μm in A, 21 μm in B, and 20 μm in C.)

Figure 3

Immunoelectron microscopy of isolated filaments from familial MSTD brain. The top and bottom panels are unlabeled, and the others are immunogold decorated with phosphorylation-dependent (AT100, AT180, AT8, and PHF1) and phosphorylation-independent (BR133 and BR134) anti-tau antibodies. (Bar = 100 nm.)

Figure 4

Immunoblotting of sarkosyl-insoluble tau from AD and familial MSTD brains. The anti-tau antibodies used were the phosphorylation-independent antisera BR134, BR304, and BR189 and the phosphorylation-dependent antibodies PHF1, AT180, AT100, AT8, and 12E8. The arrows point to the sarkosyl-insoluble tau bands of 60, 64, and 68 kDa seen in AD.

Figure 5

Immunoblots of sarkosyl-insoluble tau from familial MSTD brain before (lane 3) and after (lane 2) alkaline phosphatase treatment using antiserum BR133. Note that before alkaline phosphatase treatment, two major tau bands of 64 and 68 kDa and a minor band of 72 kDa are present; after alkaline phosphatase treatment, two major bands are visible that align with recombinant tau isoforms (lane 1) of 383 and 412 amino acids (isoforms D and E in schematic diagram).