Background: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic
projections, has been implicated in Alzheimer's disease.
Objective: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to
elucidate the tau-associated mechanism underlying cholinergic alteration.
Methods: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human
tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18
2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive
neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity
and AChE mRNA in 6 brain regions were measured.
Results: Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal
tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice
than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake
areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old
mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601
mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum.
Conclusion: The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal
cholinergic pathway in the tauopathy mouse model.