title: Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.
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.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McAlpine
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Harms
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Ruhn
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: John
authors.initials: J
authors.lastname: Hong
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Armin
authors.initials: A
authors.lastname: Blesch
authors.forename: Malú G
authors.initials: MG
authors.lastname: Tansey