A recent study led by a team of researchers at The Johns Hopkins University School of Medicine examining aging mice has provided what is believed to be the first evidence that amyloid beta protein—small, sticky protein fragment found in people with Alzheimer's disease (AD)—particles build up in the bone marrow of the animals, although not in the exact same form as the large, dense plaques found in the brains of people with Alzheimer's disease.
"Although amyloid buildup has been found in organs outside the brain—such as the heart, kidneys, and nerves—it remains unclear whether similar deposits form in bone or bone marrow with aging or in Alzheimer's disease," says contributing study author Mei Wan, Ph.D., professor of the department of Orthopaedic Surgery. While brain amyloid has been extensively studied for its role in memory loss and neurodegeneration, far less is known about amyloid elsewhere in the body. In fact, almost nothing is known about whether amyloid forms in the skeleton or how it might contribute to age-related bone loss."
AD is primarily associated with excessive amyloid plaques in the brain. Osteoporosis is a bone disease marked by low bone mineral density with an increased risk of fractures. Recent research suggests these two age-related conditions may be connected, and scientists are beginning to uncover common underlying causes.
Funded by the National Institutes of Health, the study findings, published in the July 29th edition of Nature Aging, advance scientific understanding of long-suspected similar biological processes that may be at work in osteoporosis – a form of bone loss – and Alzheimer's dementia, the researchers say. The work may also offer potential new targets for preventing or treating bone loss.
The buildup of amyloid is triggered by fat cells in the bone marrow, known as bone marrow adipocytes (BMAds), and a protein they release called SAP/PTX2 in aged mice and mice with AD. These amyloid deposits impair bone-building cells (osteoblasts) and activate bone-resorbing cells (osteoclasts), leading to bone loss. In previous mouse models, removing senescent BMAds or blocking SAP/PTX2 have shown to significantly reduce amyloid buildup and restored bone health.
In this study, male and female mice ranging from 4 to 24 months were kept in a temperature-controlled room provided with ongoing access to food and water and exposed to a 12-hour light-dark cycle. Researchers put a concentration of 5mg/ml in the drinking water of the mice aged 18 months and examined the effects CPHPC had on their age-related bone loss. CPHPC (also named Miridesap) is a small molecule compound originally designed to treat amyloidosis which is a rare disease marked by the buildup of amyloid proteins. A control group of mice aged 4, 9, 22 and 24 months were given the same dosage of water without the CPHPC drug
High-resolution imaging of thigh and shin bones revealed amyloid fibrils forming ring-like structures around BMAds in aged mice and mice genetically engineered to have a form of AD. SAP/PTX2-driven amyloid clumps were found to enhance bone loss.
Study results also showed that CPHPC successfully depleted SAP/PTX2 and reversed bone deterioration in the older mice, suggesting a promising new therapeutic strategy for osteoporosis in the elderly, a strategy that would seek to eliminate aging fat cells or amyloid-promoting proteins.
Wan adds, "Our study is what we believe to be the first to show that harmful amyloid fibers (Aβ fibrils) build up in the bone marrow of aged mice. We also found that fat cells in the bone marrow release a protein called SAP/PTX2, which plays a major role in triggering this amyloid buildup and damaging bone. These findings uncover a new connection between bone loss and dementia risk and may open the door to new research on how protecting bone health could also help protect brain function."
This discovery provides an opportunity for new treatments targeting bone aging and Alzheimer's-associated osteoporosis by focusing on the elimination of senescent fat cells or amyloid-promoting proteins.
Funding was provided by the National Institutes of Health grant R01AG068226 and R01AG072090.
In addition to Mei Wan, contributing authors included Surendra Kumar, Kangping Song, Jiekang Wang, Meghraj Singh Baghel, Yixiang Zeng, Ke Shen, Junying Zheng, Janet Crane, Shadpour Demehri, Peisong Gao, Amit Jain, Richard L. Skolasky, Philip Wong, and Xu Cao.
