The Effects of Chronic Low Back Pain on Alzheimer's Disease Progression in a Mouse Model

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Project Abstract (Supplement Project) In the elderly, the chronic low back pain (cLBP) is often comorbid with other neurodegenerative disorders including Alzheimer’s Disease (AD). The reported prevalence of chronic pain in AD patients was 45.8% with cLBP accounting for the largest proportion of the chronic pain. In the parent R01 (AR074441), we examine the effects of Receptor for Advanced Glycation End-products (RAGE) on injury-induced intervertebral disc (IVD) degeneration and low back pain. We utilize a novel retroperitoneal surgical technique for the minimally invasive and targeted injury to the mouse IVD. This surgical approach invokes a degenerative cascade that leads to behavioral symptoms of low back pain and the pathophysiological hallmarks. By leveraging the studies in the parent R01 and applying the chronic low back pain inducing intervertebral disc injury approach in a mouse model of Alzheimer’s disease, we are in a unique position to ask the question: Does chronic low back pain influence the pathology and symptom development in Alzheimer’s disease? Alzheimer’s disease is initiated by the progressive accumulation of amyloid-β (Aβ) peptide in the brain as toxic structures such as amyloid plaques and oligomers. Conversion of Aβ into these toxic species appears to be concentration-dependent; therefore, identifying mechanisms that regulate Aβ levels will provide a fundamental understanding of disease pathogenesis leading to a better evaluation of disease risk and potentially lead to new therapeutic strategies. Though Aβ is synthesized primarily within the brain, it is transported bi-directionally across the blood-brain barrier. While some transporters remove Aβ from the brain, others such as RAGE, transport Aβ from blood back into the brain. Inhibition of RAGE in mice reduces Aβ accumulation within the brain. Since RAGE is elevated in cLBP, we hypothesize that it also increases Aβ transport into brain to exacerbate Aβ pathology to increase risk of developing AD. Our studies here are also positioned to investigate whether alleviating AD pathology through RAGE inhibition can slow the progression of cLBP. This supplement draws on the expertise of unique investigators to enable new Alzheimer’s disease- focused studies to explore whether the physiology of cLBP confounds with those of AD, which will address an unmet clinical need. If indeed cLBP aggravates AD pathology and symptom development, then findings will motivate new research directions relevant to a large segment of the elderly population. This work will have significant implications in clinical care and therapeutic strategies while advancing fundamental neurobiology.