Human Apolipoprotein E4 Drives Female Disrupted Osteocyte Function and Bone Fragility

ABSTRACT: Individuals diagnosed with Alzheimers Disease - AD are at an increased risk of bone fracture. Conversely, a diagnosis of osteoporosis in females is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. In proteomic analysis of aged mouse cortical bone, we unexpectedly find several neurological disease-associated factors, including apolipoprotein E , amyloid precursor protein, and others, in the 10 percent most abundant proteins. APOE localizes specifically to bone-embedded osteocytes, with expression in aged female bone exceeding that in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate their role in bone, we used a humanized APOE knock-in mouse model that expresses the protective APOE2, neutral APOE3, or AD risk factor APOE4 alleles. APOE4 exerts strong sex-specific effects on the bone transcriptome and proteome, relative to APO2 or APOE3. APOE4-dependent disruption of the female bone proteome is an order of magnitude more severe than in hippocampus of the same mice. The APOE4 allele causes bone fragility in females, but not males, prior to age-related losses to bone mass or cognition. This bone quality deficit arises from deregulation of osteocyte function and suppression of perilacunocanalicular remodeling. Our finding suggest that osteocyte-driven regulation of bone quality is an early and under appreciated target of APOE4, preceding cognitive decline and disproportionately affecting females. Thus, bone may provide new strategies to understand and intervene in age-related cognitive decline.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling  

PROVIDER: MSV000099018 | MassIVE |

SECONDARY ACCESSION(S): PXD068037

REPOSITORIES: MassIVE