Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer's disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death.
Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform.
Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study.
Some morphometric aspects of the brain in senile dementia of the Alzheimer type.
Alzheimer's disease: cell-specific pathology isolates the hippocampal formation.
Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study.
Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease.
Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease.
Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.
Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices.
Neurofibrillary degeneration and neuronal loss in Alzheimer's disease.
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