Abstract
Alzheimer’s disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.
Highlights
In the brain without suffering significant cognitive decline or neuronal loss[6]
The lack of efficacy of drugs targeting Aβ suggests that other aspects of Alzheimer’s disease (AD) pathogenesis contribute to neuronal death
We hypothesized that dysregulated expression of cytokines secondary to glial activation during neuroinflammation contributes to AD progression by promoting neuronal death
Summary
In the brain without suffering significant cognitive decline or neuronal loss[6]. One important difference between mismatch and AD brains is that the mismatches exhibit a reduced level of neuroinflammation. There is mounting evidence, that glial responses to secreted cytokines and Aβ contribute to AD pathogenesis by producing factors, such as nitric oxygen synthase, that contribute to neuronal death[15,16] Certain cytokines, such as TNF-α , IFN-γ , and IL-6, have been implicated in neuronal death[17,18,19] and IL-6 has been reported to up-regulate amyloid precursor protein synthesis and processing[20], thereby accelerating plaque formation and disease progression. The effect of VEGF was commensurate with a broad decrease in pro-survival signaling and could be abrogated by co-application of a VEGFR1/2 inhibitor or brain-derived neurotrophic factor (BDNF) These results suggest that this pathway could be a target for AD therapy.
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