Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's disease

Neurofibrillary pathology is a characteristic hallmark of Alzheimer's disea se that is closely correlated with cognitive decline. We have analysed the density and distribution of neurofibrillary tangles (NFTs) that are immunor eactive with the monoclonal antibody (mAb) 423 in a prospectively analysed population of Alzheimer's disease (AD) cases and age-matched controls. NFTs were examined in allocortical and isocortical areas and correlated with Br aak pathological stage and clinical severity of dementia. The mAb 423 was u sed as it recognises a C-terminally truncated tau fragment that is a major constituent of NFTs. Our results show that extracellular NFTs and, to a les ser extent, intracellular NFTs, correlated significantly with both Braak st ages and the clinical index of severity. Furthermore, a differential distri bution of the two types of tangles indicates that layer II of the entorhina l cortex and the transentorhinal area are particularly vulnerable to neurof ibrillary degeneration. These areas serve as a point of connection between isocortex and hippocampus. Our findings, therefore, suggest that the perfor ant pathway may be substantially affected by the accumulation of truncated tau protein in AD and that this represents a neuropathological predictor fo r the clinical severity of dementia. When neurofibrillary pathology was exa mined by combined labelling with mAbs 423 and Alz-50 and the dye thiazin re d, we were able to demonstrate various stages of tau aggregation. The diffe rent stages may represent a sequence of conformational changes that tau pro teins undergo during tangle formation in the allocortex during the early de velopment of dementia in AD. (C) 2001 Elsevier Science B.V. All rights rese rved.