Heme and hemoglobin suppress amyloid ß-mediated inflammatory activation of mouse astrocytes.
J Biol Chem
; 293(29): 11358-11373, 2018 07 20.
Article
en En
| MEDLINE
| ID: mdl-29871926
ABSTRACT
Glial immune activity is a key feature of Alzheimer's disease (AD). Given that the blood factors heme and hemoglobin (Hb) are both elevated in AD tissues and have immunomodulatory roles, here we sought to interrogate their roles in modulating ß-amyloid (Aß)-mediated inflammatory activation of astrocytes. We discovered that heme and Hb suppress immune activity of primary mouse astrocytes by reducing expression of several proinflammatory cytokines (e.g. RANTES (regulated on activation normal T cell expressed and secreted)) and the scavenger receptor CD36 and reducing internalization of Aß(1-42) by astrocytes. Moreover, we found that certain soluble (>75-kDa) Aß(1-42) oligomers are primarily responsible for astrocyte activation and that heme or Hb association with these oligomers reverses inflammation. We further found that heme up-regulates phosphoprotein signaling in the phosphoinositide 3-kinase (PI3K)/Akt pathway, which regulates a number of immune functions, including cytokine expression and phagocytosis. The findings in this work suggest that dysregulation of Hb and heme levels in AD brains may contribute to impaired amyloid clearance and that targeting heme homeostasis may reduce amyloid pathogenesis. Altogether, we propose heme as a critical molecular link between amyloid pathology and AD risk factors, such as aging, brain injury, and stroke, which increase Hb and heme levels in the brain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Hemoglobinas
/
Astrocitos
/
Péptidos beta-Amiloides
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Citocinas
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Enfermedad de Alzheimer
/
Hemo
/
Inflamación
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2018
Tipo del documento:
Article