Analysis of the cholinergic pathology in the P301L tau transgenic pR5 model of tauopathy.

Cholinergic deafferentation of telencephalon is a major factor contributing to cognitive impairment in Alzheimer's disease. There is evidence that the degeneration of cholinergic fibers which innervate the cortex and hippocampus is due to the development of neurofibrillary tangles in the perikarya of origin. Neurofibrillary tangle formation has been modeled in the transgenic pR5 mouse strain that overexpresses the longest human tau isoform together with the P301L mutation that has been previously identified in familial cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To test the suitability of the pR5 model as a model of Alzheimer's disease concerning the cholinergic innervation of the telencephalon, we determined the expression of the human tau transgene and the presence of neurofibrillary changes in the basal nucleus of Meynert, the septal nuclei and the diagonal band of Broca, sources of cholinergic innervation of the cerebral cortex and hippocampus. We found that the cholinergic neurons of these nuclei, despite widespread expression of the human tau transgene, neither expressed human tau nor displayed immunoreactivity with antibodies AT8 and AT180 which recognize hyperphosphorylated tau. Immunoreactivity for choline-acetyl transferase did not reveal significant differences between pR5 mice and non-transgenic littermates in the basal forebrain, cortex and hippocampus. However, in the amygdala dystrophic cholinergic neurites were observed which were not present in non-transgenic mice. Our data show that although pR5 mice develop neurofibrillary lesions, they do not model the degeneration of basal forebrain cholinergic neurons observed in Alzheimer's disease.