BAG-1M co-activates BACE1 transcription through NF-κB and accelerates Aβ production and memory deficit in Alzheimer's disease mouse model.

Abstract

Accumulation of amyloid β protein (Aβ)-containing neuritic plaques in the brain is a neuropathological feature of Alzheimer's disease (AD). The β-site APP-cleaving enzyme 1 (BACE1) is essential for Aβ generation and dysregulation of BACE1 expression may lead to AD pathogenesis. Bcl-2-associated athanogen 1M (BAG-1M), initially identified as an anti-apoptotic protein, has also been found to be highly expressed in the same neurons that contain intracellular amyloid in the hippocampus of AD patient. In this report, we found that over-expression of BAG-1M enhances BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ production by up-regulating BACE1 gene transcription. The regulation of BACE1 transcription by BAG-1M was dependent on NF-κB, as BAG-1M complexes NF-κB at the promoter of BACE1 gene and co-activates NF-κB-facilitated BACE1 transcription. Moreover, expression of BAG-1M by lentiviral vector in the hippocampus of AD transgenic model mice promotes Aβ generation and formation of neuritic plaque, and subsequently accelerates memory deficits of the mice. These results provide evidence for an emerging role of BAG-1M in the regulation of BACE1 expression and AD pathogenesis and that targeting the BAG-1M-NF-κB complex may provide a mechanism for inhibiting Aβ production and plaque formation.

• Authors: Zhemin Shi, Yuheng Hong, Kun Zhang, Jingzhao Wang, Lina Zheng, Zhen Zhang, Zhimei Hu, Xiaohui Han, Yawei Han, Ting Chen, Qingbin Yao, Hongmei Cui, Wei Hong
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 9 Pg. 2398-2407 (09 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28502705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• BCL2-associated athanogene 1 protein
• DNA-Binding Proteins
• NF-kappa B
• Transcription Factors
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid Precursor Protein Secretases (biosynthesis, genetics)
• Amyloid beta-Protein Precursor (biosynthesis, genetics)
• Animals
• Aspartic Acid Endopeptidases (biosynthesis, genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Humans
• Memory Disorders (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• NF-kappa B (metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic