• Home
  • Search Results
  • Paricalcitol accelerates BACE1 lysosomal degradation and inhibits calpain-1 dependent neuronal loss in APP/PS1 transgenic mice.

Paricalcitol accelerates BACE1 lysosomal degradation and inhibits calpain-1 dependent neuronal loss in APP/PS1 transgenic mice.

EBioMedicine (2019-07-16)
Yong-Gang Fan, Tian Guo, Xiao-Ran Han, Jun-Lin Liu, Yu-Ting Cai, Han Xue, Xue-Shi Huang, Yan-Chun Li, Zhan-You Wang, Chuang Guo
ABSTRACT

Recent studies have revealed that vitamin D deficiency may increase the risk of Alzheimer's disease, and vitamin D supplementation may be effective strategy to ameliorate the neurodegenerative process in Alzheimer's disease patients. Paricalcitol (PAL), a low-calcemic vitamin D receptor agonist, is clinically used to treat secondary hyperparathyroidism. However, the potential application of PAL for treating neurodegenerative disorders remains unexplored. The APP/PS1 mice were intraperitoneally injected with PAL or vehicle every other day for 15 weeks. The β-amyloid (Aβ) production was confirmed using immunostaining and enzyme linked immunosorbent assay. The underlying mechanism was verified by western blot and immunostaining in vivo and in vitro. Long-term PAL treatment clearly reduced β-amyloid (Aβ) generation and neuronal loss in APP/PS1 transgenic mouse brains. PAL stimulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) possibly through inhibiting sterol regulatory element binding protein-2 (SREBP2); PAL also promoted LRP1-mediated β-site APP cleavage enzyme 1 (BACE1) transport to late endosomes, thus increasing the lysosomal degradation of BACE1. Furthermore, PAL diminished 8-hydroxyguanosine (8-OHdG) generation in neuronal mitochondria via enhancing base excision repair (BER), resulting in the attenuation of calpain-1-mediated neuronal loss. The present data demonstrate that PAL can reduce Aβ generation through accelerating BACE1 lysosomal degradation and can inhibit neuronal loss through suppressing mitochondrial 8-OHdG generation. Hence, PAL might be a promising agent for treating Alzheimer's disease. FUND: This study was financially supported by the Natural Science Foundation of China (U1608282).

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
1-Ethyl-2-pyrrolidone, 98%
Sigma-Aldrich
Anti-Amyloid Oligomer Antibody, αβ, oligomeric, serum, Chemicon®
Sigma-Aldrich
Anti-APP antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody
Sigma-Aldrich
Anti-RAGE, (N-terminal) antibody produced in rabbit, affinity isolated antibody