Late-onset olfactory deficits and mitral cell loss in mice lacking prion protein with ectopic expression of Doppel

Abstract

Abstract. Several lines of prion protein gene (Prnp)-knockout mice such as ZrchI, ZrchII, Npu, Ngsk and Rcm0 have been generated. Of these, ZrchII, Ngsk and Rcm0 exhibit late-onset ataxia due to ectopic expression of Doppel (Dpl); a result of damage to the splicing acceptor of Prnp exon 3. Recently, we developed another line of Prnp -/-mice (Rikn), which was generated by gene targeting with more nucleotides by replacing intron 2 with the pgk-neo gene (cf. Ngsk Prnp -/-mice) and showed not only ataxia but also a lower olfactory sensitivity than the other Prnp -/-mouse line ZrchI at over 60 weeks of age. The histopathology of the elderly Rikn Prnp -/-mice showed mitral cell loss concomitantly observed with gliosis of astrocytes. Western blot analysis showed that Dpl was detected in the cerebrum, cerebellum and olfactory bulb of Rikn Prnp -/-mice, where aberrant histopathology was observed. Thus, mitral cell loss and gliosis induced by ectopic Dpl expression were probably associated with the late-onset olfactory deficits in Rikn Prnp -/-mice.

Review of studies that have used knockout mice to assess normal function of prion protein under immunological or pathophysiological stress

“…In our previous study, Prnp −/− mice aged over 60 weeks showed not only ataxia but also poorer olfactory sensitivity than the other Prnp −/− mouse line ZrchI assessed (Fig. ) . Histopathologically, elderly Rikn Prnp −/− mice show mitral cell loss and concomitant gliosis of astrocytes.…”

Role of Cellular Prion Proteins in the Function of Macrophages and Dendritic Cells

“…Some lines of Prnp / mice (ZrchII, Ngsk, Rcm0, and Rikn) expressing the PrP-like protein Doppel (Dpl) [36], which is encoded by Prnd, exhibit a late-onset ataxia. Our line of Prnp -/-mice (Rikn) showed not only ataxia but also lower olfactory sensitivity than the other Prnp -/-mouse line ZrchI at over 60 weeks of age [46]. Furthermore, Rikn Prnp -/-splenocytes elicited lower cell proliferation rates than Prnp +/+ or Zrch I Prnp -/-splenocytes after lipopolysaccharide (LPS) stimulation and showed sporadic nerve cells in the cerebral cortex and deeper structure [47].…”

Olfactory dysfunction in the APP/PS1 transgenic mouse model of Alzheimer's disease: Morphological evaluations from the nose to the brain

“…Mitral cells send rows of axons to internal granular layer (IGl), and then transfer information to a number of areas in the brain, including the PC, EC and amygdala . It has been demonstrated that the number of mitral cells tended to reduce in the aged rodent OB, resulting in olfactory deficits . Therefore, the degeneration of mitral cells in APP/PS1 mice is also one of the factors that led to olfactory deficits.…”

“…29 It has been demonstrated that the number of mitral cells tended to reduce in the aged rodent OB, resulting in olfactory deficits. [30][31][32] Therefore, the degeneration of mitral cells in APP/PS1 mice is also one of the factors that led to olfactory deficits.…”