Structure of tau protein and assembly into paired helical filaments.

Over the past few years the systematic investigation of paired helical filament assembly from tau protein in vitro has become feasible. We review our current understanding of the structure and conformations of tau protein and how this affects tau's assembly into the pathological paired helical filaments in Alzheimer's disease.

An immunohistochemical study of centenarian brains: a comparison.

To evaluate the pathology of centenarian brains, which would reflect the ultimate stage of the aging process, 13 centenarians (M:F=1:12; mean+/-SD, 101.5+/-1.5 years) from the consecutive autopsy series were studied. None had severe dementia compatible with Alzheimer's disease (AD). As younger controls, 20 nondemented (ND) individuals (79.8+/-3.2 years) and 20 AD patients (80.8+/-3.0 years) were selected. In addition to the routine examination including methenamine-Bodian staining, an immunohistochemical study was performed, using antibodies to amyloid beta protein, tau, ubiquitin, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-MIP (a marker of the microglial and perivascular cells). No centenarian subjects satisfied the neuropathological criteria for definite AD. The densities of senile plaques and neurofibrillary tangles (NFTs) were significantly lower in almost all examined subdivisions than the AD patients, and tended to be higher than the ND subjects. Cerebral amyloid angiopathy of the centenarian was less severe than the AD patients, as well as the proliterations of GFAP-positive astrocytes and Ki-MIP-positive microglial cells, and the loss of synaptic terminal density. The relative mildness of the age-related morphological changes in the centenarians compared with the AD patients supports the idea that AD would not be the ultimate condition of the aging process, but would develop through the switching to the pathological process.

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.