Osteoblastic Swedish mutant APP expedites brain deficits by inducing endoplasmic reticulum stress-driven senescence

Selective APP_swe expression in OB-lineage cells in TgAPP
_swe
^OCN mice

To investigate osteoblastic APP_swe’s function in AD development, we took advantage of TgAPP_swe^OCN mice, in which human APP_swe expression in LSL-hAPP_swe mice depends on the removal of LSL by the OCN-Cre (Fig. 1a)²³. Although OCN-Cre mice express Cre primarily in mature/adult OB-lineage cells^27,28, our recent study showed Cre activity in neurons of dDG hippocampus, olfactory bulb, and cerebellum²⁹. Thus, it is important to verify APP_swe’s expression in bone cells and brain tissues of TgAPP_swe^OCN mice. Notice that the hAPP_swe protein was detected in the OB-lineage BMSCs (bone marrow stromal cells), but not in the hippocampus or cortex of the TgAPP_swe^OCN mice (6-MO) (Fig. 1b, c). We then asked if this is due to hAPP_swe’s cleavage (to produce Aβ₄₀ or Aβ₄₂₎…