Selective Expression of Ser 199/202 Phosphorylated Tau in a Case of Frontotemporal Dementia

Abstract

We examined a 65-year-old patient with clinicopathological features that met the criteria of frontotemporal dementia (FTD), particularly frontal lobe degeneration (FLD). He came from a family with concentrated occurrence of dementia symptoms in the presenium. Neuropathological examination disclosed brain atrophy locally pronounced on the frontotemporal lobes with characteristic neuronal loss, microvacuolation and astrocytic gliosis. There were no pathological hallmarks such as senile plaques, Pick bodies (PBs), achromatic cells and neurofibrillary tangles. Precise separation of FTD from Pick disease (PD) and motor neuron disease with dementia (MNDD) has not yet been established, and they are included in one spectrum. Antibodies against paired helical filament tau protein demonstrated immunopositive cytoskeletal structures within the neurons as well as the glial cells in the brain of the present case. They were selectively stained with tau 199/202 but not tau 396, which were provided newly to recognize phosphorylation at Ser 199/202 or Ser 396 in tau, respectively. We investigated tau pathology in the present case in comparison to 8 cases with PD that were clinicopathologically confirmed. Neither tau 199/202 nor tau 396 stained the CNS structures in PD cases with few PBs, while both stained evidently those as well as PBs in PD cases associated with many PBs; so that the present case could be distinguished from PD on the basis of the immunoreactivity to site-specific phosphorylated tau. Our result suggests that FTD, especially familial FLD type might involve unique tau pathology, no matter whether FLD is a distinct entity from PD, or a variant form in the wide FTD spectrum including PD and MNDD and other related disorders.

A novel mutation at position +12 in the intron following Exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto)

“…Degenerating neurons contained abnormal inclusions that were immunoreactive with antibodies specific for phosphorylated tau protein (see Fig 2B). As reported previously, 39 tau-positive inclusions were also present in glial cells. Classic Pick bodies, neurofibrillary tangles, and neuritic plaques were not observed.…”

“…Wide, twisted ribbons made of four-repeat tau have also been described in families with the ϩ3 and ϩ16 intronic mutations. 5,11,19,38 The tau pathology of FTD-K is both neuronal and glial, 39 as is that in other families with mutations in the intron following tau exon 10. 1,46 The discovery of mutations in the tau gene in FTDP-17 has shown that dysfunction of tau causes neurodegeneration.…”

“…Some of the clinical and neuropathological features of FTD-K have been described. 39 The pedigree is shown in Figure 1. The proband's mother, who had 8 children by two different husbands, had been healthy until death.…”

“…Magnetic resonance imaging revealed ventricular dilatation and marked brain atrophy that was most pronounced in the frontal and temporal lobes of the cerebral cortex, as presented before. 39 The proband's condition worsened significantly over the next 3 years, by which time he was severely demented and bedridden. He died of recurrent pneumonia at age 65.…”

From genotype to phenotype: A clinical, pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation

“…Immunostaining studies identified tau abnormalities in the absence of neurofibrillary tangles. 37,46,47 The biochemical data demonstrating that 4Rtau isoforms accumulate selectively as insoluble aggregates in the brains of P301L patients confirm that only those tau isoforms containing the microtubule binding repeat encoded by exon 10 (ie, 4Rtau) are affected. Because neurofibrillary tangles are composed of all six tau isoforms, the absence of neurofibrillary tangles is not surprising in these patients with FTD.…”