Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer's Disease Mice.

Abstract

BACKGROUND:

Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated.

METHODS:

The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway.

RESULTS:

Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes.

CONCLUSIONS:

These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.

• Authors: Hui Shen, Xiao-Dong Pan, Jing Zhang, Yu-Qi Zeng, Meng Zhou, Lu-Meng Yang, Bing Ye, Xiao-Man Dai, Yuan-Gui Zhu, Xiao-Chun Chen
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 129 Issue 23 Pg. 2845-2852 (12 05 2016) ISSN: 2542-5641 [Electronic] China
• PMID: 27901000 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Ddit3 protein, mouse
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Transcription Factor CHOP
• Syvn1 protein, mouse
• Ubiquitin-Protein Ligases
• Caspase 12

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Apoptosis (physiology)
• Blotting, Western
• Caspase 12 (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (physiology)
• Frontal Lobe (metabolism)
• Heat-Shock Proteins (metabolism)
• Immunohistochemistry
• Mice
• Mice, Transgenic
• Neurons (metabolism)
• Transcription Factor CHOP (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Unfolded Protein Response (physiology)