Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice

Abstract

Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in β-amyloid clearance. Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a pluripotent cytokine that has been independently involved in the pathogenesis of systemic inflammatory rheumatoid arthritis (RA) and AD. Here we first demonstrate that manipulation of peripheral TNF-α in the context of arthritis modulates the amyloid phenotype by regulating immune cell trafficking in the mouse brain. Our study suggests that additionally to its local actions in the AD brain, TNF-α can also indirectly modulate amyloid pathology as a regulator of peripheral inflammation. Our findings may have significant implications in the treatment of RA patients with anti-TNF-α drugs and in the potential use of TNF-targeted therapies for AD.

Counteracting the effects of TNF receptor‐1 has therapeutic potential in Alzheimer's disease

“…Interestingly, it has been shown that although peripheral human TNF could modulate Ab pathology by increasing the phagocytic activity of microglia, it contributes to neuronal damage and synaptic loss as well (Paouri et al, 2017a). In contrast to these results, it has also been shown that TNF inhibits phagocytosis of Ab by microglia (Koenigsknecht & Landreth, 2004).…”

“…In early AD onset, microglia may contribute to clearance of Aβ by phagocytosis, but later they initiate deleterious cascades by releasing pro‐inflammatory cytokines, which contribute to neuronal damage (Agostinho et al , ; Yang et al , ; Wang et al , ). Interestingly, it has been shown that although peripheral human TNF could modulate Aβ pathology by increasing the phagocytic activity of microglia, it contributes to neuronal damage and synaptic loss as well (Paouri et al , ). In contrast to these results, it has also been shown that TNF inhibits phagocytosis of Aβ by microglia (Koenigsknecht & Landreth, ).…”

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

“…The rats were randomly distributed into four groups: the control, control+infliximab, hyperammonemic, and hyperammonemic+infliximab group. Infliximab is an anti-TNF-a antibody that does not cross the bloodbrain barrier [40], binds to peripheral TNF-a, and reduces peripheral inflammation in rats with MHE or hyperammonemia [9,10,22]. Infliximab (Remicade; Merck Sharp & Dohme, Spain) was dissolved in saline (0.9% sodium chloride) and administered by i.v.…”

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

“…High levels of systemic TNFα can cross the blood-brain barrier (BBB), stimulating the microglia to secrete more TNFα as well as other proinflammatory factors and thus creating persistent and self-generated neuroinflammation [15]. Metabolic diseases such as obesity, hypertension, dyslipidemia, diabetes, and insulin resistance are associated with chronic systemic inflammation and a higher risk of developing neurodegenerative diseases such as Alzheimer's disease and PD [17][18][19][20][21][22][23]. Due to the importance of peripheral inflammatory processes in PD development [24][25][26], it is relevant to investigate more thoroughly the mechanisms involved.…”