Abstract
BackgroundAmyloid-beta (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD) that can lead to neuronal dysfunction and apoptosis. Tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) is an apoptotic protein that was robustly induced in the transgenic C. elegans AD brains. However, the roles of TNFAIP1 in AD have not been investigated.ResultsWe found TNFAIP1 protein and mRNA levels were dramatically elevated in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to Aβ25–35. Knockdown and overexpression of TNFAIP1 significantly attenuated and exacerbated Aβ25–35-induced neurotoxicity in N2a cells, respectively. Further studies showed that TNFAIP1 knockdown significantly blocked Aβ25–35-induced cleaved caspase 3, whereas TNFAIP1 overexpression enhanced Aβ25–35-induced cleaved caspase 3, suggesting that TNFAIP1 plays an important role in Aβ25–35-induced neuronal apoptosis. Moreover, we observed that TNFAIP1 was capable of inhibiting the levels of phosphorylated Akt and CREB, and also anti-apoptotic protein Bcl-2. TNFAIP1 overexpression enhanced the inhibitory effect of Aβ25–35 on the levels of p-CREB and Bcl-2, while TNFAIP1 knockdown reversed Aβ25–35-induced attenuation in the levels of p-CREB and Bcl-2.ConclusionThese results suggested that TNFAIP1 contributes to Aβ25–35-induced neurotoxicity by attenuating Akt/CREB signaling pathway, and Bcl-2 expression.
Highlights
Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD) that can lead to neuronal dysfunction and apoptosis
We examined the roles of TNFAIP1 in Aβ25–35-induced apoptosis in neuronal cell line by testing whether the neuronal apoptosis induced by Aβ25–35 is associated with the expression of TNFAIP1 protein, and if so, whether apoptosis can be blocked by inhibition of TNFAIP1 expression using TNFAIP1 siRNA
Aβ25–35 induces TNFAIP1 expression To determine whether Aβ25–35 can increase the TNFAIP1 protein expression, mouse primary cortical neurons were treated with Aβ25–35 at different doses for 24 h, and Western blot was used to examine TNFIAP1 protein level
Summary
Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD) that can lead to neuronal dysfunction and apoptosis. Alpha-induced protein 1 (TNFAIP1) is an apoptotic protein that was robustly induced in the transgenic C. elegans AD brains. The 37–43 amino acid Aβ fragments in the brain are originally derived from the β-amyloid precursor protein (APP) via proteolytic processing by β- and γ-secretase [4]. Liu et al BMC Neurosci (2016) 17:51 conserved single-copy gene [9], implying that TNFAIP1 has an important physiological role, which is yet to be explored. The transcription levels of TNFAIP1 had been found to be robustly induced in the transgenic C. elegans AD brains and post-mortem AD brain [13, 14], suggesting TNFAIP1 may involve in the process of AD development. The role of TNFAIP1 in AD has not been demonstrated
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