Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology

NEUROBIOLOGY OF DISEASE

卷:34

Article

McAlpine, Fiona E.¹  Lee, Jae-Kyung¹  Harms, Ashley S.¹  Ruhn, Kelly A.¹  Blurton-Jones, Mathew²  Hong, John¹  Das, Pritam³  Golde, Todd E.³  LaFerla, Frank M.²  Oddo, Salvatore²  Blesch, Armin⁴  Tansey, Malu G.¹ 

[1] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[2] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

[3] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[4] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

关键词: Neuroinflammation;    Alzheimer's disease;    Tumor necrosis factor;    3xTgAD;    Amyloid-beta;    Amyloid precursor protein;    beta-CTF;    Lentivirus;   

DOI  :  10.1016/j.nbd.2009.01.006

来源: Elsevier

【 摘 要 】

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 A beta 40 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. (C) 2009 Elsevier Inc. All rights reserved.

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