The Potential Influence of Bone-Derived Modulators on the Progression of Alzheimer’s Disease

Abstract

Bone, the major structural scaffold of the human body, has recently been demonstrated to interact with several other organ systems through the actions of bone-derived cells and bone-derived cell secretory proteins. Interestingly, the brain is one organ that appears to fall into this interconnected network. Furthermore, the fact that osteoporosis and Alzheimer's disease are two common age-related disorders raises the possibility that these two organ systems are interconnected in terms of disease pathogenesis. This review focuses on the latest evidence demonstrating the impact of bone-derived cells and bone-derived proteins on the central nervous system, and on how this may be relevant in the progression of Alzheimer's disease and for the identification of novel therapeutic approaches to treat this neurodegenerative disorder.

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

“…Patients with less brain atrophy show better bone quality [ 76 ], indicating central mechanisms of AD contributing to bone loss [ 7 ]. Further, patients suffering from AD or mild cognitive impairments display higher levels of osteopontin [ 77 ], which correlates with cognitive decline [ 78 ] and reduced BMD [ 79 ], while AD progression is linked to serum levels of the bone turnover markers osteopontin, osteocalcin and sclerostin [ 8 ]. In AD, an accumulation of extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions causing cell degeneration has been observed [ 80 ].…”

“…In the brain, Wnt/β-catenin signaling is essential for neurogenesis, neuronal survival, synaptic plasticity, BBB integrity [ 82 ] and further associated with the pathophysiology of AD [ 354 ]. As SOST /sclerostin is expressed by several other tissues in physiological and pathogenic conditions [ 355 ], additional studies are required to elucidate whether pharmacologic inhibition of sclerostin may also affect Wnt/β-catenin signaling in the brain [ 8 ].…”

“…In addition to the molecular mediators secreted by bone, bone marrow-derived cells were identified to enter the systemic circulation and migrate into the injured brain [ 8 ]. In preclinical studies, bone marrow-derived microglia-like cells were shown to modulate amyloid pathology by restricting Aβ plaque formation and by supporting Aβ plaque clearance, which improved cognitive impairment [ 366 , 367 , 368 ].…”

“…Additionally, the systemic transplantation of bone marrow-derived macrophages reduced neuroinflammation with a limited reversion of Aβ deposition [ 370 ]. In summary, growing evidence of experimental AD studies demonstrates the capacity of bone marrow-derived microglia and macrophages to enter the CNS and to suppress the progression of brain degeneration, which provides a promising therapeutic tool for AD patients [ 8 , 371 ].…”

“…Although brain and bone seem apparently unrelated, exceptional clinical and experimental evidence propose a bilateral dependence of both organs [ 1 , 2 ]. The effect of brain on bone homeostasis and regeneration, transmitted via the ‘efferent’ nervous system, is well established [ 3 , 4 , 5 ] whereas the understanding of the ‘afferent’ effect of bone on brain function and development is still evolving [ 6 , 7 , 8 ]. Therefore, multiple stress, mood and neurodegenerative brain pathologies were previously correlated with bone loss, while only a limited number of genetic skeletal diseases was associated with the modulation of brain development and function.…”