Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology
Fiona E McAlpine, Jae-Kyung Lee, Ashley S Harms, Kelly A Ruhn, Mathew Blurton-Jones, John Hong, Pritam Das, Todd E Golde, Frank M LaFerla, Salvatore Oddo, Armin Blesch, Malú G Tansey, Fiona E McAlpine, Jae-Kyung Lee, Ashley S Harms, Kelly A Ruhn, Mathew Blurton-Jones, John Hong, Pritam Das, Todd E Golde, Frank M LaFerla, Salvatore Oddo, Armin Blesch, Malú G Tansey
Abstract
Microglial activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in Alzheimer's disease (AD). Elevated levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) have been reported in serum and post-mortem brains of patients with AD, but its role in progression of AD is unclear. Using novel engineered dominant negative TNF inhibitors (DN-TNFs) selective for soluble TNF (solTNF), we investigated whether blocking TNF signaling with chronic infusion of the recombinant DN-TNF XENP345 or a single injection of a lentivirus encoding DN-TNF prevented the acceleration of AD-like pathology induced by chronic systemic inflammation in 3xTgAD mice. We found that chronic inhibition of solTNF signaling with either approach decreased the LPS-induced accumulation of 6E10-immunoreactive protein in hippocampus, cortex, and amygdala. Immunohistological and biochemical approaches using a C-terminal APP antibody indicated that a major fraction of the accumulated protein was likely to be C-terminal APP fragments (beta-CTF) while a minor fraction consisted of Av40 and 42. Genetic inactivation of TNFR1-mediated TNF signaling in 3xTgAD mice yielded similar results. Taken together, our studies indicate that soluble TNF is a critical mediator of the effects of neuroinflammation on early (pre-plaque) pathology in 3xTgAD mice. Targeted inhibition of solTNF in the CNS may slow the appearance of amyloid-associated pathology, cognitive deficits, and potentially the progressive loss of neurons in AD.
Figures
![Figure 1. Hippocampal infusion of XENP345 attenuates…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0001.jpg)
![Figure 2. Hippocampal infusion of XENP345 reduces…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0002.jpg)
![Figure 3. In vitro validation of the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0003.jpg)
![Figure 4. ICV administration of Lenti-DN-TNF results…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0004.jpg)
![Figure 5. ICV administration of Lenti-DN-TNF attenuates…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0005.jpg)
![Figure 6. Relative abundance of APP, C-terminal…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0006.jpg)
![Figure 7. solTNF inhibition reduces accumulation of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0007.jpg)
![Figure 8. Genetic deletion of TNFR1 in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2948857/bin/nihms-211696-f0008.jpg)
Source: PubMed