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

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

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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / immunology
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases* / immunology
  • Amyloid Precursor Protein Secretases* / metabolism
  • Amyloid beta-Peptides* / immunology
  • Amyloid beta-Peptides* / metabolism
  • Amyloid beta-Protein Precursor / immunology
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases* / immunology
  • Aspartic Acid Endopeptidases* / metabolism
  • Autoantibodies* / blood
  • Autoantibodies* / immunology
  • Brain / immunology
  • Brain / metabolism
  • Brain / pathology
  • Cohort Studies
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic*
  • Middle Aged

Substances

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Autoantibodies
  • BACE1 protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Bace1 protein, mouse