Gonzalez C E, Schurman C A, Wilson K A, Schilling B, Ellerby L M, Tang S Y
Department of Biomedical Engineering, Washington University in St Louis, St. Louis, MO.
Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO.
bioRxiv. 2025 Jun 10:2025.05.24.655931. doi: 10.1101/2025.05.24.655931.
Chronic low back pain, frequently associated with intervertebral disc (IVD) degeneration, is highly prevalent in individuals with Alzheimer's disease (AD), and the pain intensity is highly correlated with the degree of cognitive impairment. While the incidences of both afflictions increase dramatically in the elderly population, it is unknown whether AD exacerbates the health of the IVD. Utilizing one-year-old male and female 5xFAD mice that constitutively express human APP and PSEN1 transgenes with five AD-linked mutations, we measured the lumbar IVD's extracellular matrix composition, the three-dimensional structure, histopathological degeneration, and mechanical behavior. The collagen, glycosaminoglycans, and advanced glycation end-products content of the IVD were not appreciably different between the 5xFAD animals and their wild-type littermates. Likewise, the 5xFAD IVDs were not histopathologically degenerated. However, the IVD volume, measured by contrast-enhanced microCT, was larger in the 5xFAD animals. Furthermore, dynamic microcompression revealed that 5xFAD IVDs exhibited higher loss tangent, indicating altered tissue damping and fluid-flow dynamics within the disc. These results suggest that although the IVDs of mice with AD are not more degenerated, they may be more susceptible to damage accumulation due to the elevated absorption of energy. Elderly individuals with AD may thus be more prone to IVD injuries that lead to eventual degeneration and spinal pain. Future work will focus on defining the molecular mechanisms and the consequences of these mechanical and structural changes in the IVD and their consequences to low back pain in individuals with AD.
慢性下腰痛常与椎间盘退变相关，在阿尔茨海默病（AD）患者中极为普遍，且疼痛强度与认知障碍程度高度相关。虽然这两种疾病在老年人群中的发病率都急剧上升，但尚不清楚AD是否会加剧椎间盘的健康问题。我们利用一岁的雄性和雌性5xFAD小鼠，这些小鼠组成性表达带有五个与AD相关突变的人类APP和PSEN1转基因，测量了腰椎间盘的细胞外基质组成、三维结构、组织病理学退变和力学行为。5xFAD小鼠及其野生型同窝小鼠的椎间盘胶原蛋白、糖胺聚糖和晚期糖基化终产物含量没有明显差异。同样，5xFAD小鼠的椎间盘在组织病理学上也没有退变。然而，通过对比增强微CT测量，5xFAD小鼠的椎间盘体积更大。此外，动态微压缩显示5xFAD小鼠的椎间盘损耗角正切更高，表明椎间盘内的组织阻尼和流体流动动力学发生了改变。这些结果表明，虽然患有AD的小鼠的椎间盘退变程度并不更高，但由于能量吸收增加，它们可能更容易积累损伤。因此，患有AD的老年人可能更容易发生椎间盘损伤，最终导致退变和脊柱疼痛。未来的工作将集中于确定椎间盘这些力学和结构变化的分子机制及其后果，以及它们对AD患者下腰痛的影响。
