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

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 β-amyloid protein (Aβ₁₋₄₂) and tau. The excess Aβ₁₋₄₂ 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/IFNγ-stimulated human microglia. We found that the CM caused a large increase in the production and release of Aβ and tau. The CM also caused SH-SY5Y cells to increase their expression of amyloid precursor protein and release of its β-secretase cleaved products (sAPPβs) as well as Aβ oligomers, but the CM reduced release of its α-secretase cleaved products (sAPPαs). Direct treatment of SH-SY5Y and N-tera2 cells with the inflammatory cytokines IL-6 and IL-1β as well as with Aβ₁₋₄₂, resulted in an increase in tau messenger RNA and protein expression. Pretreatment of LPS/IFNγ-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 Aβ₁₋₄₂. Our data indicate that reactive microglia play an important role in governing the expression of Aβ and tau, and therefore the progression of AD. They provide further evidence that appropriate anti-inflammatory treatment should be beneficial in AD.