Targeting TNF: a therapeutic strategy for Alzheimer's disease

Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

“…TNF reduces Ab phagocytosis by cultured microglial cells, along with scavenger receptors used for its uptake, possibly by shifting microglia into a pro-inflammatory state or phenotype (Hickman et al, 2008;Koenigsknecht-Talboo and Landreth, 2005;Townsend et al, 2005). TNF is generally thought to be detrimental for Alzheimer's disease, particularly its soluble form, since TNF overexpression worsens disease (Janelsins et al, 2008), and TNF inhibition confers some improvement in Tg models and human patients (Cheng et al, 2014;He et al, 2007;McAlpine et al, 2009;Shi et al, 2011). However, TNF in itself is not necessarily detrimental and may be neuroprotective (Lambertsen et al, 2009).…”

“…Since proinflammatory cytokines such as TNF might affect the progression of Alzheimer's disease (Cheng et al, 2014), we examined how TNF expression changed with age in WT and APP/PS1 Tg mice, and whether TNF mRNA levels correlated with % Ab plaque load and soluble Ab42 and Ab40. Compared to 3-month-old mice, we found statistically significant increases in TNF mRNA levels at 21 months of age in WT mice by qPCR, and as early as 9 months of age in APP/PS1 Tg mice, reaching a maximum 8-fold increase at 21 months ( Fig.…”

“…While early studies did not detect TNF immunoreactivity in Alzheimer's brains (Hofman et al, 1989;Selmaj et al, 1991), or found that TNF protein was reduced (Lanzrein et al, 1998), other studies have shown increased TNF in brains and CSF from Alzheimer's patients (Dickson et al, 1993;Tarkowski et al, 1999;Wilberding et al, 2008). Furthermore, a significant role for TNF in Alzheimer's disease is implicated by findings of improved cognitive function in Alzheimer's patients treated with anti-TNF agents (Cheng et al, 2014). Increased cytokine expression, along with microglial reactivity, is also found in patients with mild cognitive impairment (MCI) and non-demented individuals with high Alzheimer's pathology (Cagnin et al, 2001;Tarkowski et al, 2003;Wilberding et al, 2008), indicating that inflammation might also play an important role in the early stages of Alzheimer's disease.…”

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

“…44,46,54,[76][77][78][79] Altered activation of both TNF-α and WNT5A signalling has been found in the brains of patients with several types of neurodegenerative disorders. [80][81][82] Assuming that the TNF-α and WNT5A-mediated cell cycle dysfunction reported here could be peripheral sign of FTLD associated with PGRN deficiency, we think that targeting TNF-α and/or WNT5A signalling could have potential implications for designing novel therapeutic strategies.…”

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

“…This prompted us to explore in further detail the mechanisms responsible for the A␤-lowering properties of nilvadipine and to identify a possible molecular target controlling both A␤ production, A␤ clearance across the BBB, and Tau hyperphosphorylation. As (Ϫ)-nilvadipine and racemic nilvadipine inhibit BACE-1 transcription, we evaluated whether (Ϫ)-nilvadipine was impacting NFB activation because NFB has been shown to play an important role in the regulation of BACE-1 transcription and expression (36,37,43,44). We observed that (Ϫ)-nilvadipine inhibits NFB activation in response to TNF␣ (Fig.…”