Myeloproliferative blood cancers as a human neuroinflammation model for development of Alzheimer’s disease: evidences and perspectives

Abstract

Chronic inflammation and involvement of myeloid blood cells are associated with the development of Alzheimer's disease (AD). Chronic inflammation is a highly important driving force for the development and progression of the chronic myeloproliferative blood cancers (MPNs), which are characterized by repeated thrombotic episodes years before MPN-diagnosis, being elicited by elevated erythrocytes, leukocytes, and platelets. Mutations in blood cells, the JAK2V617F and TET2-mutations, contribute to the inflammatory and thrombogenic state. Herein, we discuss the MPNs as a human neuroinflammation model for AD development, taking into account the many shared cellular mechanisms for reduction in cerebral blood, including capillary stalling with plugging of blood cells in the cerebral microcirculation. The therapeutic consequences of an association between MPNs and AD are immense, including reduction in elevated cell counts by interferon-alpha2 or hydroxyurea and targeting the chronic inflammatory state by JAK1-2 inhibitors, e.g., ruxolitinib, in the future treatment of AD.

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

“…Herein, we argue for the rationales and perspectives for initiating clinical studies on the safety and efficacy of rIFN-β -a forgotten drug in the treatment of cancer, but hopefully soon to be revived for the treatment of patients with MPNs, in whom repeated ischemic strokes contribute significantly to morbidity and mortality. From this perspective, repurposing rIFN-β in the treatment of MPNs is expected to open a new horizon for MPN patients, taking into account that rIFN-β may not only be highly efficacious in controlling elevated blood cell counts, but may also play a neuroprotective role—not only against the development of Alzheimer’s disease [ 129 ], but also in ischemic stroke prevention [ 210 ].…”

“…The potential of rIFN-β in the treatment of neuroinflammatory diseases other than MS, such as Alzheimer’s disease (AD), has also been investigated [ 127 , 128 ]. Since AD and MPNs share several pathogenetic mechanisms, MPNs have most recently been described as “A Human Neuroinflammation Model for The Development of Alzheimer’s Disease” [ 129 ]. Herein, after briefly depicting the successful history of rIFN-α in the treatment MPNs, we tell the story of rIFN-β in other diseases and discuss the rationales and perspectives for launching studies on the safety and efficacy of pegylated IFN-β in the treatment of MPNs.…”

Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

“…Most lately, the MPNs have been described as a human neuroinflammation model for the development of Alzheimer's disease. 33 Accordingly, it is intriguing to use MPNs as a "Human inflammation model" on drusen/AMD development as well, implying CLI in MPNs to elicit drusen formation, which "triggers" more CLI, creating a vicious cycle.…”

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

“…The pathogenetic role of inflammation has been emphasized in the initiation and progression of disease, as well as in the development of the typical signs/symptoms of MPNs, such as anemia, constitutional symptoms, thrombosis, splenomegaly, BM fibrosis and pulmonary hypertension, thus actively contributing to morbidity and mortality [ 29 , 30 , 31 , 32 ]. Moreover, for some authors, MPNs epitomize a full-fledged inflammatory model of human cancer development, as suggested by the evidence of abnormal cytokine production and an association with several inflammatory/autoimmune diseases and second cancers [ 33 , 34 , 35 , 36 , 37 , 38 ]. In this model, chronic inflammation is hypothesized to induce the first oncogenic hit in the HSC by causing mutations and genomic instability, eventually leading to MPN emergence [ 39 , 40 ].…”