Abstract
While opiates like morphine play a major role in the pharmacotherapy for the control of pain associated with various diseases, paradoxically, their long-term use is associated with cognitive impairments. Furthermore, morphine administration has been shown to result in neuronal synaptodendritic injury in rodent brains, leading to neurodegeneration. We recently reported the role of astrocytes as contributors of amyloidosis associated with HIV-associated neurological disorders. Herein we hypothesize that morphine could induce astrocytic amyloidosis, which, in turn, could be disseminated to various regions in the brain by astrocyte-derived EVs (ADEVs). In this study we demonstrate brain region-specific up-regulation of astrocytic amyloids in morphine dependendent rhesus macaques. In addition, herein we also demonstrate increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to morphine. Mechanisms involved in this process included the up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the promoter of BACE1, leading to increased BACE1 activity and, generation of Aβ 1-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1 mediated amyloidosis leading to astrocyte activation and neuroinflammation. We next sought to assess whether morphine-stimulated ADEVs could carry amyloid cargoes. Results showed that morphine exposure induced the release of morphine-ADEVs, carrying amyloids. Interestingly, silencing HIF-1α in astrocytes not only reduced the numbers of ADEV released, but also the packaging of amyloid cargos in the ADEVs. These findings were further validated in brain derived EVs (BEVs) isolated from macaques, wherein it was shown that BEVs from morphine-dependent macaques, carried varieties of amyloid cargoes including the cytokine IL-1β. This is the first report implicating the role of HIF-1α-BACE1 axis in morphine-mediated induction of astrocytic amyloidosis, leading, in turn, to neuroinflammation and release of the amyloid cargoes via ADEVs. These findings set the groundwork for the future development of therapeutic strategies for targeting cognitive deficits in chronic opiate users.
Highlights
While opiates like morphine play a major role in the pharmacotherapy for the control of pain associated with various diseases, paradoxically, their long-term use is associated with cognitive impairments
In our recent report we showed that HIV-1 protein Tat induced astrocytic amyloidosis involving the HIF-1αBACE1-AS axis, leading to the development of Alzheimer’s Disease (AD)- like pathology in both HIV-1+ patients and in SIV-infected macaques, that was linked with HIV-associated neurological disorders (HAND) [26]
Increased expression of the cleaved toxic Amyloid β (Aβ) 1–42 form, resulting in astrogliosis and neuroinflammation. We found that these amyloids and neuroinflammatory cargoes were packaged in the astrocyte-derived Extracellular Vesicles (EVs) (ADEVs) and released to the extracellular space (ECS), which could contribute to neurodegeneration and neuroinflammation involving the HIF-1α-BACE1 axis
Summary
While opiates like morphine play a major role in the pharmacotherapy for the control of pain associated with various diseases, paradoxically, their long-term use is associated with cognitive impairments. We demonstrate increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to morphine Mechanisms involved in this process included the up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the promoter of BACE1, leading to increased BACE1 activity and, generation of Aβ 1-42. In our recent report we showed that HIV-1 protein Tat induced astrocytic amyloidosis involving the HIF-1αBACE1-AS axis, leading to the development of AD- like pathology in both HIV-1+ patients and in SIV-infected macaques, that was linked with HIV-associated neurological disorders (HAND) [26]. There are no reports on the role of morphine in astrocytic amyloidosis, leading to neuroinflammation which, in turn, could manifest as cognitive impairments
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