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. 2024 Oct 24;148(1):57.
doi: 10.1007/s00401-024-02814-x.

Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer's disease

Ye-Ran Wang #  1   2   3 , Xiao-Qin Zeng #  1   2 , Jun Wang  1   2 , Christopher J Fowler  4 , Qiao-Xin Li  4 , Xian-Le Bu  1   2 , James Doecke  5 , Paul Maruff  4   6 , Ralph N Martins  7   8 , Christopher C Rowe  9 , Colin L Masters  10 , Yan-Jiang Wang  11   12   13 , Yu-Hui Liu  14   15
Affiliations

Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer's disease

Ye-Ran Wang et al. Acta Neuropathol. .

Abstract

The profile of autoantibodies is dysregulated in patients with Alzheimer's disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET- CN, 169 Aβ-PET+ cognitively normal subjects (preclinical AD), and 31 Aβ-PET+ cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.

Keywords: Alzheimer’s disease; Autoantibodies; Aβ amyloid; BACE1; Cognitive impairment.

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References

    1. Alexopoulos P, Thierjung N, Grimmer T, Ortner M, Economou P, Assimakopoulos K et al (2018) Cerebrospinal fluid BACE1 activity and sAβPPβ as biomarker candidates of Alzheimer’s disease. Dement Geriatr Cogn Disord 45:152–161. https://doi.org/10.1159/000488481 - DOI - PubMed
    1. Aprahamian T, Bonegio RG, Richez C, Yasuda K, Chiang LK, Sato K et al (2009) The peroxisome proliferator-activated receptor gamma agonist rosiglitazone ameliorates murine lupus by induction of adiponectin. J Immunol 182:340–346. https://doi.org/10.4049/jimmunol.182.1.340 - DOI - PubMed
    1. Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y et al (2011) A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med 3:84ra43. https://doi.org/10.1126/scitranslmed.3002254 - DOI - PubMed
    1. Bettcher BM, Tansey MG, Dorothee G, Heneka MT (2021) Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus. Nat Rev Neurol 17:689–701. https://doi.org/10.1038/s41582-021-00549-x - DOI - PubMed - PMC
    1. Bristol JA, Brand J, Ohashi M, Eichelberg MR, Casco A, Nelson SE et al (2022) Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells. PLoS Pathog 18:e1010453. https://doi.org/10.1371/journal.ppat.1010453 - DOI - PubMed - PMC

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