Activated human microglia stimulate neuroblastoma cells to upregulate production of beta amyloid protein and tau: implications for Alzheimer's disease pathogenesis

作者：Lee Moonhee; McGeer Edith; McGeer Patrick L^*

来源：Neurobiology of Aging, 2015, 36(1): 42-52.

DOI：10.1016/j.neurobiolaging.2014.07.024

• Amyloid precursor protein
• Tauopathy
• Ibuprofen
• Aspirin
• Glutathione
• Neurofibrillary tangles
• IL-10

Neuroinflammation is hypothesized to be a major driving force behind Alzheimer's disease (AD) pathogenesis. This hypothesis predicts that activated microglial cells can stimulate neurons to produce excessive amounts of beta-amyloid protein (A beta(1-42)) and tau. The excess A beta(1-42) forms extracellular deposits which stimulate further microglial activation. The excess tau is partially released but also becomes phosphorylated forming intracellular neurofibrillary deposits. The end result is a positive feedback mechanism which drives the disease development. To test the viability of this hypothesis, we exposed differentiated SH-SY5Y and N-tera2/D1 (N-tera2) cells to conditioned medium (CM) from LPS/IFN gamma-stimulated human microglia. We found that the CM caused a large increase in the production and release of A beta and tau. The CM also caused SH-SY5Y cells to increase their expression of amyloid precursor protein and release of its beta-secretase cleaved products (sAPP beta s) as well as A beta oligomers, but the CM reduced release of its alpha-secretase cleaved products (sAPP alpha s). Direct treatment of SH-SY5Y and N-tera2 cells with the inflammatory cytokines IL-6 and IL-1 beta as well as with A beta(1-42), resulted in an increase in tau messenger RNA and protein expression. Pretreatment of LPS/IFN gamma-stimulated human microglia cells with the nonsteroidal anti-inflammatory drugs ibuprofen and aspirin, the antioxidant GSH, the H2S donor NaSH, and the anti-inflammatory cytokine IL-10, resulted in a CM with diminished ability to stimulate tau expression. There was no effect on the morphology of SH-SY5Y cells, or on their viability, following exposure to micromolar levels of A beta(1-42). Our data indicate that reactive microglia play an important role in governing the expression of A beta and tau, and therefore the progression of AD. They provide further evidence that appropriate anti-inflammatory treatment should be beneficial in AD.

• 出版日期2015-1