Presenilin L166P Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss

Q: What bone changes are observed early in familial Alzheimer’s disease models in this study?

Female PSEN1/hAPP Tg+ mice exhibit reduced whole-body bone mineral density and bone mineral content, and PSEN1 KI mice lacking hAPP show low bone mass and reduced bone microarchitecture as early as one month.

Q: How do the authors explain the mechanism behind reduced bone mass?

The study attributes reduced bone microarchitecture largely to decreased bone formation, indicated by lower serum P1NP levels and reduced osteoblast ALP activity and gene expression in vitro, alongside hormonal changes such as increased FSH.

Q: Do the findings involve both bone and brain expression of relevant proteins?

Yes. Western blotting identifies both PSEN1 and amyloid-beta protein expression in bone and brain tissue, supporting crosstalk between mutant PSEN1 actions and systemic effects.

Sep 30, 2026

Uploaded by Rowan

Accelerated bone loss is reported in early Alzheimer’s disease, with reduced bone mineral density and higher fracture risk than in healthy individuals. This study examines bone loss in mouse models of familial Alzheimer’s disease carrying the Presenilin 1 (L166P) knock-in mutation, with or without the human APP transgene that induces brain amyloid pathology by six months. Female PSEN1/hAPP Tg+ mice show reduced whole-body bone mineral density and bone mineral content versus controls. PSEN1 KI mice lacking hAPP also display low bone mass and impaired microarchitecture as early as one month, with evidence for diminished bone formation and systemic hormonal effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Background on Alzheimer’s disease and fracture risk

Links between dementia progression and bone mineral density

Comprehensive Physiology RESEARCH ARTICLE OPEN ACCESS Presenilin L166P Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss Vidyani Suryadevara1 | Connor J. Krehbial2 | Anuradha K. Valiya1 | Melinda Vang3 | Julian Balanta-Melo4,5 | Pierre P. Eleniste3 | Sumana Posritong3 | Jung Min Hong3 | Katie Chester3 | Gabriel M. Pagnotti4 | Teresita Bellido5,6 | Monte S. Willis1,5 | Angela Bruzzaniti3,5 1Department of Pathology and Laboratory Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA | 2Department of Biomedical Engineering, Indiana University School of Medicine, Indianapolis, Indiana, USA | 3Department of Biomedical and Applied Sciences, School of Dentistry, Indiana University, Indianapolis, Indiana, USA | 4Department of Endocrine, Neoplasia and Hormonal Disorders, University of Texas-MD Anderson Cancer Center, Houston, Texas, USA | 5Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, Indiana, USA | 6Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, Indiana, USA Correspondence: Vidyani Suryadevara ([vidyani@stanford.edu](vidyani@stanford.edu)) | Angela Bruzzaniti ([abruzzan@iu.edu](abruzzan@iu.edu)) Received: 14 November 2025 | Revised: 22 December 2025 | Accepted: 24 December 2025 Keywords: aging | Alzheimer's disease | bone mass | mechanical function | presenilin 1 | sex hormones ABSTRACT Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with PSEN1 L166P driving the phenotype, female PSEN1 KI mice lacking the hAPP transgene also displayed low bone mass with a reduction in bone microarchitecture observed as early as 1 month of age. Correspondingly, PSEN1 KI mice exhibit reduced cortical and trabecular bone mass compared to age-and sex-matched control mice. The loss of bone microarchitecture was largely attributed to a reduction in bone formation as indicated by decreases in serum P1NP levels and osteoblast ALP activity and mRNA expression in vitro. At the ages examined, PSEN1 KI mice exhibited increased follicle stimulating hormone (FSH) levels, which is known to cause a decrease in bone mass. Western blotting also identified both PSEN1 and amyloid-beta protein expression in bone and brain tissue. Taken together, the data indicate that female-specific bone loss in familial AD is potentially due to the direct actions of mutant PSEN1 in bone cells combined with systemic crosstalk caused by brain-expressed PSEN1 L116P. | Abbreviations: AD, Alzheimer's disease; ALP, alkaline phosphatase activity; APP, amyloid precursor protein; Aβ, amyloid-beta; BMC, bone mineral content; BMD, bone mineral density; Ct, cortical; CTX-1, carboxy-terminal collagen type-1 crosslink fragments; DEXA, Dual-energy X-ray absorptiometry; E2, estrogen; FSH, follicle stimulating hormone; M-CSF, Macrophage Colony Stimulating Factors; P1NP, procollagen type I N propeptide; PSEN1, presenilin 1; PTH, parathyroid hormone; Tb, trabecular; TRAP, tartrate-resistant acid phosphatase; 􀀟CT, microCT.
Monte S. Willis and Angela Bruzzaniti contributed equally to this article. | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.<

FAQs

What bone changes are observed early in familial Alzheimer’s disease models in this study?

Female PSEN1/hAPP Tg+ mice exhibit reduced whole-body bone mineral density and bone mineral content, and PSEN1 KI mice lacking hAPP show low bone mass and reduced bone microarchitecture as early as one month.

How do the authors explain the mechanism behind reduced bone mass?

The study attributes reduced bone microarchitecture largely to decreased bone formation, indicated by lower serum P1NP levels and reduced osteoblast ALP activity and gene expression in vitro, alongside hormonal changes such as increased FSH.

Do the findings involve both bone and brain expression of relevant proteins?

Yes. Western blotting identifies both PSEN1 and amyloid-beta protein expression in bone and brain tissue, supporting crosstalk between mutant PSEN1 actions and systemic effects.

Sep 30, 2026

Uploaded by Rowan