BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides.

Publisher: BioMed Central Country of Publication: England NLM ID: 101266600 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1326 (Electronic) Linking ISSN: 17501326 NLM ISO Abbreviation: Mol Neurodegener Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2006-

Alzheimer Disease*/metabolism ; Amyloid beta-Peptides*/metabolism; Animals ; Mice ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Astrocytes/metabolism ; Clusterin/metabolism ; Mice, Knockout ; Mice, Transgenic

Background: Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer's disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions.
Methods: We conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates. Similar scRNA-seq was also conducted using AD mice with conditional deletion of Bace1 in the adult stage (5xFAD;Bace1 ^fl/fl ;UBC-creER compared to 5xFAD;Bace1 ^fl/fl controls). We compared the transcriptomes of astrocyte and reactive astrocyte clusters and identified several differentially expressed genes, which were further validated using Bace1 KO astrocyte cultures. Mice with astrocyte-specific Bace1 knockout in 5xFAD background were used to compare amyloid deposition. Mechanistic studies using cultured astrocytes were used to identify BACE1 substrates for changes in gene expression and signaling activity.
Results: Among altered genes, Clusterin (Clu) and Cxcl14 were significantly upregulated and validated by measuring protein levels. Moreover, BACE1 deficiency enhanced both astrocytic Aβ uptake and degradation, and this effect was significantly attenuated by siRNA knockdown of Clu. Mechanistic study suggests that BACE1 deficiency abolishes cleavage of astrocytic insulin receptors (IR), and this may enhance expression of Clu and Cxcl14. Acutely isolated astrocytes from astrocyte-specific knockout of Bace1 mice (Bace1 ^fl/fl ;Gfap-cre) show similar increases in CLU and IR. Furthermore, astrocyte-specific knockout of Bace1 in a 5xFAD background resulted in a significant attenuation in cortical Aβ plaque load through enhanced clearance.
Conclusion: Together, our study suggests that BACE1 in astrocytes regulates expression of Clu and Cxcl14, likely via the control of insulin receptor pathway, and inhibition of astrocytic BACE1 is a potential alternative strategy for enhancing Aβ clearance.
(© 2023. The Author(s).)

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RF1 AG058261 United States AG NIA NIH HHS

Keywords: Amyloid plaques; Aβ clearance; BACE1; CXCL14; Clusterin; Insulin receptor; Reactive astrocytes

0 (Amyloid beta-Peptides)
0 (Amyloid beta-Protein Precursor)
EC 3.4.- (Amyloid Precursor Protein Secretases)
EC 3.4.23.- (Aspartic Acid Endopeptidases)
EC 3.4.23.46 (Bace1 protein, mouse)
0 (Clusterin)
0 (Clu protein, mouse)

Date Created: 20230504 Date Completed: 20230511 Latest Revision: 20230511

20250114

PMC10161466

10.1186/s13024-023-00611-w

37143090