# Cortical Bone Loss and Fragility in a 2-Month Triple Transgenic Mouse Model of Alzheimer’s Disease

## TL;DR

This study shows that a mouse model of Alzheimer’s disease shows early bone loss and weaker bones before brain symptoms appear.

## Contribution

The study reveals early skeletal changes in a triple transgenic Alzheimer’s model before brain pathology emerges.

## Key findings

- 3xTg-AD mice show reduced cortical bone mass and mechanical strength at 2 months.
- Increased osteoclasts and empty osteocyte lacunae suggest imbalanced bone resorption.
- Bone changes occur before β-amyloid plaques or cognitive decline are detectable.

## Abstract

What are the main findings?
Characterization of the skeletal phenotype of 3xTg-AD mice with reduced cortical bone mass and decreased mechanical properties.Two-month-old male 3xTg-AD mice are characterized by an increased Number of Empty Osteocytic Lacunae and Osteoclasts, and a reduction of TRAP+ Osteocytes.

Characterization of the skeletal phenotype of 3xTg-AD mice with reduced cortical bone mass and decreased mechanical properties.

Two-month-old male 3xTg-AD mice are characterized by an increased Number of Empty Osteocytic Lacunae and Osteoclasts, and a reduction of TRAP+ Osteocytes.

What is the implication of the main findings?
3xTg-AD mice exhibit early skeletal fragility before the appearance of typical brain lesions.This skeletal fragility could be attributed to an imbalanced process of osteocyte osteolysis.

3xTg-AD mice exhibit early skeletal fragility before the appearance of typical brain lesions.

This skeletal fragility could be attributed to an imbalanced process of osteocyte osteolysis.

Alzheimer’s disease (AD) and osteoporosis frequently co-occur in the elderly; however, the pathophysiological link between these two diseases remains unclear. This study investigates skeletal alterations in a triple transgenic 3xTg-AD mouse model of AD (3xTg-AD), which harbors mutations in β-amyloid precursor protein (βAPPSwe), presenilin-1 (PS1M146V), and tauP301L, and recapitulates key aspects of AD pathology, including age-dependent β-amyloid plaque accumulation and cognitive decline. To assess early skeletal changes, we analyzed femurs and tibiae of 2-month-old male non-Tg and 3xTg-AD mice (n = 9/group) using micro-CT. Despite the absence of β-amyloid plaques at this stage, 3xTg-AD mice showed significant cortical bone loss, with reduced bone surface, periosteal and endosteal perimeters, total and cortical cross-sectional area, and polar moment of inertia. The 3-point-bending test confirmed compromised mechanical properties, including reduced maximum load-to-fracture and stiffness. Histological analyses highlighted an increased number of Empty Osteocyte Lacunae, reduced TRAP+ osteocytes, and an elevated number of osteoclasts; such evidence indicates impaired osteocyte function and increased bone resorption. These findings indicate that cortical bone loss and compromised mechanical properties occur before detectable neuropathological hallmarks in this AD model.