Sex-specific transcriptomic profiling reveals key players in bone loss associated with Alzheimer's disease

Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is frequently associated with musculoskeletal complications, including sarcopenia and osteoporosis, which substantially impair patient quality of life. Despite these clinical observations, the molecular mechanisms linking AD to bone loss remain insufficiently explored. In this study, we examined the femoral bone microarchitecture and transcriptomic profiles of APP/PS1 transgenic mouse models of AD to elucidate the disease's impact on bone pathology and identify potential gene candidates associated with bone deterioration. We performed micro-computed tomography (microCT) and RNA transcriptome analysis on the femoral bone of these mice. We observed a significant reduction in bone microstructure in both male and female APP/PS1 mice compared to their wild-type counterparts. Transcriptomic analysis of femoral bone tissue revealed substantial differential gene expression between AD mice and controls. Specifically, APP/PS1 mice exhibited differential expression in 289 protein-coding genes across both sexes. Notably, in female APP/PS1 mice, 664 genes were differentially expressed, with key genes such as Shh, Efemp1, Arg1, EphA2, Irx1, and PORCN potentially implicated in bone loss. In male APP/PS1 mice, 787 genes were differentially expressed, with Sel1l, Ffar4, Hspa1a, AMH, WFS1, and CLIC1 emerging as notable candidates in the context of bone deterioration. Gene Ontology (GO) enrichment analysis further revealed distinct sex-specific gene pathways between male and female APP/PS1 mice, underscoring the differential molecular underpinnings of bone pathology in AD. This study identifies novel sex-specific genes in the APP/PS1 mouse model and proposes potential therapeutic targets to mitigate bone loss in AD patients.

Keywords: APP/PS1 mice; Alzheimer’s disease; Bone loss.

Fig. 1

Effects of Alzheimer’s disease on the bone structural quality of male (upper panel) and female (lower panel) femurs measured by micro-computed tomography. a Bone mineral density (BMD), b bone volume to total volume (BV/TV), c bone volume, d bone surface, e trabecular thickness (Tb. Th), f trabecular number (Tb.N), g trabecular separation (Tb.Sp) in males and h BMD, i BV/TV, j bone volume, k bone surface, l Tb. Th, m Tb.N, n Tb.Sp in females. Black circles (WT mice, male n = 7, female n = 4) and red squares (APP/PS1, male n = 7, female n = 5) represent the number of mice for each sex. Data were analyzed by Student’s t-test for two groups (*p < 0.04, **p < 0.01)

Fig. 2

Heat maps show differential gene expression in femurs of a wild-type (WT) vs APP/PS1 mice (n = 8 for both groups), b wild-type vs APP/PS1 female mice (n = 4 for both groups), and c wild-type vs APP/PS1 male mice (n = 4 for both groups). Shades of blue indicate positive z-scores, while orange depicts negative z-scores

Fig. 3

Gene Ontology (GO) analysis revealed enriched gene sets that differed between wild-type and APP/PS1 a female and b male mice. List of novel genes with potential connections to bone loss in AD in c female and d male mice. Highlight gene sets potentially uncovering pathways that are sex specific and may have a role in AD-related pathology

Fig. 4

Schematic diagram showing sex-specific alteration in signaling pathways in the bone transcriptome of APP/PS1 mice