Dysfunction of the cholinergic system of the basal forebrain complex is one of the major contributors toward cognitive impairment in Alzheimer's disease (AD). In AD, degeneration of cholinergic fibers that project to the cerebral cortex and hippocampus may be attributed to the development of neurofibrillary tangles (NFT). Here, we evaluated the relationship between neurofibrillary changes and degeneration of septal cholinergic neurons in P301L tau transgenic mice. The number of cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB) in the basal forebrain was significantly reduced in P301L mice compared with age-matched wild-type mice. The phospho-tau levels and NFT formation in these P301L mice were higher than those in wild-type mice. However, it is still unknown how the development of NFT is caused in AD and AD-like pathology. Our results show that Fas-associated factor 1 (FAF1) expression as well as caspase-3 activation were increased in AT8-positive MS/VDB cholinergic neurons. Furthermore, the formation of AT8-positive paired helical filaments increased in proportion to FAF1 expression and caspase-3 activation in MS/VDB cholinergic neurons. On the basis of the collective findings, we suggest that increased FAF1 expression triggers caspase-3 cleavage and activation, leading to hyperphosphorylated tau aggregation and subsequent NFT formation, in turn initiating apoptosis in MS/VDB cholinergic neurons.