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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.

SUBMITTER: McAlpine FE

PROVIDER: S-EPMC2948857 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

McAlpine Fiona E FE Lee Jae-Kyung JK Harms Ashley S AS Ruhn Kelly A KA Blurton-Jones Mathew M Hong John J Das Pritam P Golde Todd E TE LaFerla Frank M FM Oddo Salvatore S Blesch Armin A Tansey Malú G MG

Neurobiology of disease 20090401 1

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 wit ...[more]

PMID: 19320056

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Project description:Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-? (A?) peptide. Accumulation of A?, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110? isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APPswe/PS1?E9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K? (?D910A) had reduced A? peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K? inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted A? peptide. Importantly, APP/PS1/?D910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K? as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.SIGNIFICANCE STATEMENT During Alzheimer's disease (AD), the accumulation of the toxic amyloid-? (A?) peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both A? plaque load and neuroinflammation holds therapeutic promise. Using a combination of genetic and pharmacological approaches, we found that the p110? isoform of phosphoinositide 3-kinase (PI3K) is involved in anterograde trafficking of the amyloid precursor protein in neurons and in the secretion of tumor necrosis factor-alpha from microglial cells. Genetic inactivation of PI3K? reduces A? plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3K? represents a novel therapeutic approach to ameliorate AD pathology by dampening plaque accumulation and microglial-dependent neuroinflammation.

Project description:Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

Dataset Information

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

Publications

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

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