GSK-3 β is a serine/threonine kinase, involved in several signaling pathways such as cell proliferation and inflammation (Cui et al., 1998; Park et al., 2006). Notably, GSK-3β appears to be responsible for tau hyperphosphorylation (Sperber et al., 1995), detaching tau from microtubules and inducing tau precipitation as intracellular neurofibrillary tangles (NFTs; Ferrer et al., 2002), a hallmark of AD. Moreover, GSK-3β has been shown to mediate the release of inflammatory cytokines in LPS-activated microglia in vitro (Green and Nolan, 2012), thus GSK-3 could be a promising target. Tideglusib (NP031112), a thiadiazolidinine derivative, prevents inflammation and neurodegeneration in a kainic-acid inflammation rat model (Luna-Medina et al., 2007) and has reached phase II clinical trials on AD patients (Clincaltrials.gov identifier NCT00948259), appearing safe though not effective enough (del Ser et al., 2013; Lovestone et al., 2015). In another study, two triazolopyridine derivative GSK-3 inhibitors (C-7a and C-7b) reduced Aβ neurotoxicity and tau hyperphosphorylation in vitro and improved cognitive deficits in a transgenic AD mouse model (Noh et al., 2013), though no anti-inflammatory effects were investigated. More recently, triazinones displayed in vitro anti-GSK-3 and anti-BACE-1 activity plus neuroprotective and neurogenic effects besides good brain permeability in vivo (Prati et al., 2015), however no anti-inflammatory data are currently available. Lastly, L807mts, a highly selective GSK-3 peptide derivative inhibitor, reduced Aβ levels, reduced inflammation and enhanced autophagy in a transgenic AD mouse model (Licht-Murava et al., 2016).

Aβ aggregates are generated by the cleavage of the membrane-associated APP by α, β and γ-secretases. Through two successive proteolytic cleavages by α-secretase and γ-secretase, a harmless peptide, p3, is produced. On the other hand, β-secretase operates a different cleavage leading to the production of two neurotoxic peptides of 40 and 42 amino acids each, called Aβ40 and Aβ42, respectively. The first β–secretase identified was BACE-1, a type I transmembrane aspartic protease (Vassar et al., 1999). Because Aβ can induce neuroinflammation, BACE-1 inhibitors can contribute indirectly to inhibiting microglial M1 activation and research on their potential application is ongoing. In vivo treatment with the aminoisoindole AZ-4217, a BACE-1 inhibitor, resulted in long term reduced Aβ deposition in an APP transgenic cerebral amyloidosis mouse model (Eketjäll et al., 2013). In another study, treatment with the BACE inhibitor RO5508887 reduced amyloid plaque load and formation in an AD transgenic mouse model and combined treatment with an anti-Aβ antibody (gantenerumab) further enhanced these effects (Jacobsen et al., 2014), however the impact on cognition was not investigated. Also, as previously stated, triazinones displayed anti-GSK-3 and anti-BACE-1 activity (Prati et al., 2015) while NB-360, another BACE-1 inhibitor was able to block Aβ deposition and the accumulation of inflammatory cells in a transgenic AD mouse model (Neumann et al., 2015). Noteworthy, a clinical trial to study the effect of the BACE-1 inhibitor LY3202626 on patients with mild AD dementia, as of February 2017 was recruiting patients (Clinicaltrials.gov identifier NCT02791191).

Mitogen-activated protein kinases (MAPKs) are serine–threonine kinases that mediate intracellular signaling. JNK is a major cellular stress response protein induced by oxidative stress and its activation is believed to be an early event in AD (Zhu et al., 2001). Among the MAPKs, JNK is one of the essential mediators of microglial proinflammatory functions (Waetzig et al., 2005), it is a component of signaling pathways that lead to inflammation, and it can control the synthesis and release of proinflammatory molecules by LPS-activated microglia (Hidding et al., 2002). Moreover, the JNK-AP1 signaling pathway mediates the increased expression of inflammatory genes induced by Aβ peptides in human brain endothelial cells and in AD brain (Vukic et al., 2009). Thus JNK is an attractive target for AD prevention/therapy. In one study, treatment of LPS-activated primary rat microglia with conserved dopamine neurotrophic factor (CDNF) resulted in reduced production of inflammatory cytokines by suppressing the phosphorylation of JNK and thus inhibiting JNK signaling (Zhao et al., 2014). Therefore, CDNF use in vivo seems promising. Another recent in vivo study showed that administration of the JNK inhibitor SP600125 resulted in cognitive deficit improvement in a transgenic AD mouse model by reducing Aβ production, inflammatory responses and synaptic loss (Zhou et al., 2015). Interestingly, in vivo administration of the small molecule LX2343 improved cognitive deficits in a transgenic AD mouse model by inhibiting both JNK and BACE-1 activity, reducing Aβ production and promoting autophagy (Guo et al., 2016), though no direct anti-inflammatory mechanisms were investigated.

PDEs act as regulators of intracellular signaling cascades through the control of 2 second messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Recent findings point to PDE inhibitors as compounds able to affect different mechanisms underlying AD, as shown by active ongoing research with these molecules. Administration of sildenafil, a PDE-5 inhibitor, improved cognitive deficits, reduced Aβ levels and neuroinflammation in a transgenic AD mouse model (Zhang et al., 2013). Moreover, administration of another PDE-5 inhibitor, yonkenafil, resulted in improved cognitive function, increased neurogenesis in the dentate gyrus and reduced activation of microglia and astrocytes in a transgenic AD mouse model (Zhu et al., 2015), therefore showing also anti-inflammatory effects. In another study, the PDE-7 inhibitor S14 improved cognitive impairment, reduced Aβ deposition and tau phosphorylation in a transgenic AD mouse model (Perez-Gonzalez et al., 2013). Also in an in vitro study, the PDE-3 inhibitor cilostazol reduced Aβ production by increasing ADAM10 expression (Lee et al., 2014), though no anti-inflammatory effects were investigated. Noteworthy, a phase IV clinical trial to examine the additive effects of cilostazol on donepezil-treated mild to moderate AD patients has been completed (Clinicaltrials.gov identifier NCT01409564) and in a very recent small clinical trial, cilostazol administration as an add-on therapy reduced cognitive decline in AD patients (Tai et al., 2017). In another study, administration of GEBR-7b, a PDE-4D inhibitor, improved cognitive deficits in a transgenic AD mouse model (Sierksma et al., 2014) though the underlying mechanisms of action remain to be discovered. Lastly, in a very recent in vivo study, administration of the PDE-4 inhibitor FFM reversed cognitive deficits in a transgenic AD mouse model by increasing CREB phosphorylation and BDNF levels and reducing inducible NO synthase (iNOS), TNF-α and IL-1β levels (Guo et al., 2017).

AMPK is a highly conserved energy sensor involved in mitochondrial biogenesis, cellular stress responses and regulation of inflammation (Corton et al., 1994; Zong et al., 2002; Giri et al., 2004). Because overactivated AMPK has been reported to accumulate in neurons containing tangles in AD brains (Vingtdeux et al., 2011) and AMPK can phosphorylate tau protein (Domise et al., 2016), AMPK may represent an interesting target, though its role in AD is not fully understood. While inhibition of AMPK with the compound C (CC) improved hippocampal synaptic plasticity impairment induced by Aβ in a transgenic AD mouse model (Ma et al., 2014) AMPK activators have also shown beneficial effects in AD models. An example are the anti-epileptic drugs topiramate and levetiracetam which improved cognitive deficits, reduced Aβ production, increased the activation of AMPK and inhibited HDAC activity in a transgenic AD mouse model (Shi et al., 2013). Moreover, a phase II levetiracetam clinical trial on MCI patients was completed in 2012, though no results were posted (Clinicaltrials.gov identifier NCT01044758). Also, while not tested in AD, telmisartan, an angiotensin II type 1 receptor blocker, increased brain AMPK activation and microglial M2 gene expression in an LPS-induced neuroinflammation mouse model (Xu et al., 2015) thus its application in AD may deserve attention. In another study, administration of the AMPK activator AICAR, improved cognitive deficits in a streptozotocin-induced AD rat model (Du et al., 2015) by restoring mitochondrial functions, though no anti-inflammatory effects were investigated. Lastly, treatment with the small molecule THSG exerted anti-inflammatory effects on LPS-activated microglia by reducing iNOS, COX-2, TNF-α and IL-6 levels and increased AMPK phosphorylation levels, thus confirming AMPK activation (Park et al., 2016).

The effects of histone acetylation on the activation of gene expression were unknown until the 1960s (Allfrey et al., 1964). Acetylation reduces the positive charge of basic histone proteins thus decreasing their interaction with DNA and allowing gene expression. More in detail, this process is finely regulated by several Histone Acetyl Transferases (HATs) and HDACs. Recently, the effects of HDAC inhibitors on immunomodulation have increasingly generated interest due to a potential role in immunotherapy. In fact, class I HDAC inhibitors have been reported to increase transcription of neuronal genes, provide neuroprotective effects, and enhance cognitive abilities. Moreover, class I HDAC inhibitors such as valproic acid (VPA), trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), sodium phenylbutyrate (SB) and MS-275 have been shown to enhance neurite outgrowth, synaptic plasticity, neurogenesis, neuronal differentiation and axon regeneration in cultured neurons and in vivo (Laeng et al., 2004; Siebzehnrubl et al., 2007; Koriyama et al., 2014). In one in vivo study, administration of the HDAC inhibitor SB, prevented cognitive deficits and reduced Aβ and GFAP levels, suggesting an anti-inflammatory effect in a transgenic AD mouse model (Ricobaraza et al., 2011). Another in vivo study showed that treatment with the benzamide HDAC inhibitor MS-275 improved cognitive deficits and reduced microglial activation and Aβ accumulation in a transgenic AD mouse model (Zhang and Schluesener, 2013). Lastly, in another in vivo study, SAHA treatment restored H3 acetylation and BDNF levels (Sharma and Taliyan, 2016) in mice fed a fat-enriched diet which developed insulin resistance-induced cognitive decline. While not being an AD study, insulin resistance is considered a risk factor for AD (Fava et al., 2017) and thus SAHA may deserve attention in AD research.

PPAR-γ is a nuclear receptor that, after binding peroxisome proliferators, binds to specific DNA PPAR response elements regulating the expression of genes involved in fatty acid peroxisomal beta-oxidation (Dreyer et al., 1993). Current evidence shows that PPAR-γ activation may prove useful in AD therapy. In one in vitro study pioglitazone, a PPAR-γ agonist, inhibited iNOS and the production of IL-1β, TNF-α and IL-6 in LPS-activated HAPI microglia (Ji et al., 2010). Unfortunately, a phase II pioglitazone clinical trial performed in mild to moderate AD patients completed in 2009 produced no results (Clinicaltrials.gov identifier NCT00982202). In another in vitro study, the small molecule SNU-BP inhibited inflammatory cytokine production and iNOS in LPS-stimulated microglia by activating PPAR-γ. SNU-BP also increased IL-4 and arginase-1 expression, considered as M2 microglial phenotype markers (Song et al., 2016), thus SNU-BP may deserve in vivo testing as well. Interestingly, PPAR-γ agonists able to act on other targets are also being studied in AD therapy. Such is the case for T3D-959, a PPAR-γ and PPAR-δ agonist that reversed neurodegeneration in a streptozotocin-induced AD mouse model though no anti-inflammatory mechanisms were investigated (Tong et al., 2016). Noteworthy, a phase II clinical trial focused on TD3D-959 in mild to moderate AD patients as of June 2016 was being performed (Clinicaltrials.gov identifier NCT02560753). Lastly, MH84 a PPAR-γ agonist/γ-secretase modulator, reduced Aβ42 in HEK293APPwt cells, characterized by elevated Aβ42 levels, and improved mitochondrial dysfunction (Pohland et al., 2016), thus performing in vivo MH84 studies applied to AD therapy may be worth.

Well-known carotenoids such as β-carotene, lycopene and lutein can be found in carrots, tomatoes, peaches and peppers among other foods (Lozano et al., 2016). Lycopene, highly concentrated in tomatoes, was able to reduce BV-2 microglial cell activation after LPS treatment in vitro by reducing COX-2 expression (Lin et al., 2014). Moreover, lycopene exerted anti-inflammatory effects and enhanced cognitive performance in a Aβ42-induced AD rat model by downregulating inflammatory cytokines such as TNF-α and IL1-B (Sachdeva and Chopra, 2015). Also lutein, highly present in parsley, was able to reduce LPS-induced neuroinflammation in BV-2 microglial cells, by significantly inhibiting iNOS and cyclooxygenase-2 activity, as well as by reducing TNF-α and IL-1β production (Wu et al., 2015). However, no in vivo data on the anti-inflammatory effect of lutein are currently available. Interestingly, a human study involving nearly 7000 participants aged 50 or older found an association between high levels of serum lycopene and lutein and a lower risk of mortality by AD (Min and Min, 2014). Current research on AD and bioactive compounds has also focused on less-known carotenoinds. For example, fucoxanthin, a carotenoid abundant in brown seaweeds, exerted anti-inflammatory effects and reduced reactive oxygen species levels in Aβ42 treated BV2 microglial cells (Pangestuti et al., 2013). Moreover, in another in vitro inflammation-induced microglial cell culture study, fucoxanthin was able to inhibit the secretion of inflammatory cytokines after LPS treatment (Zhao et al., 2017). However, no in vivo data on the anti-inflammatory effect of fucoxanthin are currently available.

On the other hand, carotenoids contained in saffron, such as crocin and crocetin, exerted in vitro anti-inflammatory effects on LPS-treated rat brain microglial cells by inhibiting NO synthesis from iNOS and the production of inflammatory cytokines (Nam et al., 2010). Also, in another study, trans-crocetin was able to improve Aβ degradation in monocytes derived from AD patients (Tiribuzi et al., 2017) thus it would be interesting to determine whether trans-crocetin may induce the same effect in microglia. Remarkably, crocin intraperitoneal administration showed neuroprotective effects in vivo, by blocking Aβ-induced apoptosis in an AD animal model (Asadi et al., 2015) which means crocin is able to cross the blood brain barrier, despite its hydrophilic nature.

Phytosterols such as β-sitosterol, stigmasterol and campesterol can be found in vegetable oils, such as olive oil, cereals, legumes and nuts (Lozano et al., 2016). While a direct anti-inflammatory activity in AD has not been reported for most phytosterols, their anti-inflammatory effects may not have been thoroughly investigated. Stigmasterol, one of the most prevalent phytosterols in foods, exhibited beneficial effects in vivo in an AD animal model, mainly by reducing Aβ generation (Burg et al., 2013). In another in vivo study, a plant sterol-enriched diet was able to prevent cognitive impairment in SAMP8 mice, a non-transgenic AD animal model. This beneficial effect could derive from the fact that plant sterols may substitute lost cholesterol in SAMP8 mice brains (Pérez-Cañamás et al., 2016). AD studies have also focused on less common phytosterols. For example, spinasterol, isolated from Aster scaber, widely used in Korean cuisine, exerted anti-inflammatory effects on LPS-activated BV-2 microglial cells by upregulating heme-oxygenase-1 and reducing the production of TNF-α, IL-1β and PGE2 (Jeong et al., 2010). However, no anti-inflammatory effects for spinasterol in aging/AD models have been reported. Moreover, fucosterol, a phytosterol contained in brown seaweed, exerted anti-inflammatory effects on RAW264.7 macrophages by inhibiting the production of NO and the expression of iNOS and cyclooxygenase-2 (Jung et al., 2013). This suggests that fucosterol may exert the same anti-inflammatory effects on microglial cells. Interestingly, a recent in vitro study additionally shows that fucosterol may also exert BACE-1 inhibitory effects (Jung et al., 2016).

Phenolic compounds such as tyrosol, capsaicin, coumaric, caffeic and chlorogenic acid can be found in citrus, olives, oats and soybeans wheras polyphenols, the most heterogeneous group of bioactive compounds, which includes quercetin, rutin, flavan-3-ols, catechins, anthocyanins, flavones (luteolin), isoflavones (phytoestrogens such as genistein, daidzein), curcumin and lignans can be found in onions, blueberries, red wine and tea (Lozano et al., 2016). Chemically speaking, phenolic acids belong to the supercategory of polyphenols, and thus we describe several examples together. In one in vitro study, caffeic acid, naturally present in honeybee propolis, exerted anti-inflammatory effects on BV-2 microglia by inhibiting the expression of iNOS and cyclooxygenase-2 (Tsai et al., 2015). Moreover, caffeic acid oral administration improved cognitive deficits in an Aβ25–35-induced AD animal model, possibly by inhibiting lipid peroxidation and NO production (Kim et al., 2015).

In another study, artoindonesianin O, a phenolic compound found in mulberries, blocked Aβ-42 toxicity in an in vitro model of AD (Qiao et al., 2015). While no in vivo anti-inflammatory properties for artoindonesianin O have been reported, a recent report showed that artoindonesianin O is a potent lipooxygenase inhibitor, thus it could also play an anti-inflammatory role in vivo (Lang et al., 2016).

On the other hand, carnosic acid found in rosemary and sage, was able to inhibit LPS-induced activation of MG6 microglial cells in vitro, by reducing iNOS levels (Yanagitai et al., 2012). Moreover, carnosic acid was able to improve cognitive deficits in an Aβ40-induced AD rat model (Rasoolijazi et al., 2013). In another study, oral administration of ferulic acid, found in seeds and cereals, particularly flaxseed (Beejmohun et al., 2007), inhibited microglial activation in an Aβ42-induced AD mouse model by decreasing IFN-gamma levels in the hippocampus (Kim et al., 2004). Moreover, ferulic acid administration was able to improve cognitive deficits in a transgenic AD mouse model (Mori et al., 2013).

Interest in the application of other polyphenols normally present in foods for AD research has constantly increased. In fact, oral administration of oleuropein aglycone, found in olive leaves, significantly attenuated astrocyte and microglial activation in an Aβ42-induced AD rat model (Luccarini et al., 2014). Moreover, oleuropein aglycone oral administration also improved cognitive deficits and reduced Aβ42 plaque area and number in a transgenic AD mouse model (Pantano et al., 2017). Also resveratrol, a polyphenol found in red grapes and wine, was able to inhibit Aβ-induced activation of BV-2 microglial cells by reducing the production of inflammatory factors such as TNF-α, IL-1β and NO (Yao et al., 2015). Moreover, resveratrol administration showed anti-inflammatory and anti-apoptotic effects in vivo in an Aβ42-induced AD mouse model by inhibiting PDE-4 signaling (Wang et al., 2016). Interestingly, dietary resveratrol also extended life span of SAMP8 mice, a non-transgenic AD mouse model through sirtuin activation (Porquet et al., 2013). However, a resveratrol phase II clinical trial on patients with mild to moderate AD, resulted in no benefit to patients (Turner et al., 2015; Clinicaltrials.gov identifier NCT01504854).

In another study, curcumin, mainly found in turmeric, inhibited Aβ induced microglial activation in vitro (Shi et al., 2015). Moreover, curcumin administration improved cognitive deficits in an AD transgenic rat model, possibly through an anti-inflammatory effect by activating PPAR-gamma (Liu et al., 2016) and a phase II curcumin clinical trial on mild to moderate AD patients was concluded in 2009 though no results were posted (Clinicaltrials.gov identifier NCT00099710).

Regarding phytoestrogens, genistein, the main isoflavone found in soy, exerted anti-inflammatory effects on LPS-activated BV-2 microglia by blocking TLR4 signaling (Jeong et al., 2014). Moreover, genistein improved cognitive deficits in an AD mouse model (Bonet-Costa et al., 2016). However, oral administration of soy isoflavones (100 mg/day) to AD patients for 6 months resulted in no cognitive deficit improvement (Gleason et al., 2015; Clinicaltrials.org identifier NCT00205179). This could be due to the fact that genistein is metabolized by the gut microbiome to its most active metabolite, equol, only in presence of specific bacteria in the gut microbiome such as Slackia isoflavoniconvertens (Matthies et al., 2009).

In another study, anthocyanin in vitro treatment inhibited LPS-induced BV-2 microglial activation by reducing IL-1β levels (Meireles et al., 2016). Moreover, a diet supplemented with 1% anthocyanin extracts was able to prevent cognitive deficits in a transgenic AD mouse model (Yamakawa et al., 2016) whereas pomegranate polyphenol administration exerted anti-inflammatory effects on a transgenic AD mouse model by reducing TNF-α brain levels and microgliosis (Rojanathammanee et al., 2013).

Even the polyphenol epigallocatechin from green tea, attenuated Aβ EOC 13.31 microglial activation in vitro (Cheng-Chung Wei et al., 2016). While no in vivo anti-inflammatory effects for green tea catechins in AD have been reported, green tea epicatechin administration combined with treadmill exercise improved cognitive deficits in an AD transgenic mouse model (Zhang et al., 2016). Also, a phase II epigallocatechin clinical trial on early stage AD patients was completed on 2016 though no results have been published yet (Clinicaltrials.gov identifier NCT00951834).

Lastly, rutin, a citrus flavonoid, exerted anti-inflammatory and antioxidant effects in an AD transgenic mouse model, improving spatial memory (Xu et al., 2014).

Interestingly, one in vivo study showed that dietary polyphenols may exert in part their beneficial effects after being converted into phenolic acids by intestinal microbiota (Wang et al., 2015).

Sulfur compounds such as glucosinolates (isothiocyanate, sulphoraphane) and Allium genus compounds (allin, allicin and ajoene) can be found in cabbage, broccoli, onions and garlic (Lozano et al., 2016). Sulforaphane, an isothiocyanate derived from glucoraphanin hydrolysis in broccoli, exerted anti-inflammatory effects in vitro on LPS-activated microglia by decreasing IL-1β, IL-6 and TNF-α expression (Brandenburg et al., 2010). Moreover, sulforaphane was able to extert anti-inflammatory effects against Aβ42-induced microglial activation in THP-1 macrophages through STAT-1 dephosphorylation and the activation of heme-oxygenase 1 (An et al., 2016). While no in vivo anti-inflammatory effects in AD disease have been reported for sulforaphane, sulforaphane administration exerted neuroprotective effects in an AD aluminum-induced mouse model (Zhang et al., 2015). Moreover, a very recent study showed that treatment with moringin, an isothiocyanate derived from the edible plant Moringa oleifera, exerted potent in vitro ant-inflammatory effects on LPS-activated RAW 264.7 macrophages (Giacoppo et al., 2017). Also, moringin showed in vivo anti-inflammatory effects in a Parkinson’s disease mouse model (Giacoppo et al., 2017) and thus it would be worth testing moringin also on aging and AD models.