Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer's disease progression

Nat Metab. 2024 Mar;6(3):531-549. doi: 10.1038/s42255-024-00989-x. Epub 2024 Feb 26.

Abstract

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

MeSH terms

  • Aging
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid Precursor Protein Secretases / therapeutic use
  • Amyloid beta-Peptides / therapeutic use
  • Animals
  • Aspartic Acid Endopeptidases / metabolism
  • Aspartic Acid Endopeptidases / therapeutic use
  • Cognition
  • Female
  • Humans
  • Male
  • Mice
  • Osteocytes / metabolism
  • Osteocytes / pathology
  • Wnt Signaling Pathway
  • beta Catenin / metabolism
  • beta Catenin / therapeutic use

Substances

  • Amyloid beta-Peptides
  • Amyloid Precursor Protein Secretases
  • beta Catenin
  • Aspartic Acid Endopeptidases