Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging - LOAD

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SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia in the elderly and the vast majority of patients are designated as non-genetically dependent Late-Onset AD (LOAD). Several studies have shown increased risk of fracture with dementia owing in part to increases in falls. On the flip side, several clinical studies have also demonstrated that a fracture history can increase the risk for dementia. Historically, the most widely used mouse models relevant to AD have used transgenic approaches to induce relevant pathologies in young mice. Unfortunately, transgenic overexpression animal models do not effectively produce the heterogeneity observed clinically in LOAD patients and thus are not ideal for therapy development or evaluation. Hence, the NIA-funded Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) Center is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant risk factors. One such mouse model is the aging LOAD mouse (hAbeta/APOE4/Trem2*R47H, Jax #030670). Therefore, as a logical extension of our parent R01 (AG060621), in this AD Supplement, we propose to examine the impact of fracture and our novel fracture therapies on neuroinflammation and the associated cognitive decline in aging LOAD mice. Our parent R01 focuses on developing novel drug therapies such as Sirt1 activator, SRT1720 and thrombopoietic agents to improve fracture healing outcomes in old mice. We found that SRT1720 administered systemically, TPO delivered locally, and TPO mimetic peptides (TMP) delivered systemically were able to improve bone healing. Based on these observations, we hypothesize that fracture increases age-dependent neuroinflammation and cognitive decline in LOAD mice. We further hypothesize that treatment of aging fractured or unfractured LOAD mice with SRT1720 or TMP will reduce neuroinflammation and slow cognitive decline. One Aim is proposed in this Supplement. Aim 1. Determine the effects of a femoral fracture and treatment of femoral fractures with SRT1720 or TMP on neuroinflammation and cognitive decline in aging LOAD mice. To accomplish this aging LOAD mice will undergo baseline cognitive testing. Half of the mice will serve as uninjured controls and half of the mice will undergo a surgically induced femoral fracture. Mice will be treated with SRT1720, TMP, or vehicle control beginning at the time of surgery until mice are euthanized 6 months post- surgery. Fracture healing, cognitive decline, neuroinflammation, the integrity of the Blood Brain Barrier (BBB) will be assessed. Successful completion of this Supplement will determine whether fracture results in more rapid cognitive decline in a novel LOAD mouse model recently developed and characterized by the MODEL-AD consortium. Importantly these studies may demonstrate that treatment with novel bone healing therapies SRT1720 and/or TMP, which are known to improve fracture healing, may have the added benefit of slowing the cognitive decline associated with LOAD.