The potential use of natural killer cells to treat Alzheimer's disease: Can nutrition play a role?

Abstract

According to the World Health Organization (WHO), dementia is a significant cause of disability and dependency among older individuals globally (Wortmann, 2012). Among the various types of dementia, Alzheimer's disease (AD) is the most prevalent, accounting for over 60% of cases (2020). It is important to note that AD cases can be categorized into two main types: early-onset familial AD, which accounts for less than 1% of cases, and late-onset sporadic AD, which comprises approximately 95% of cases (Drummond & Wisniewski, 2017).

The hallmark characteristics of AD are the presence of extracellular amyloid β (Aβ) plaques and intraneuronal phosphorylated tau (p-Tau) aggregates, known as neurofibrillary tangles (Yeh et al., 2017). Neurons in the brain produce significant amounts of Aβ (Busciglio et al., 1993). Microglia, which are the macrophages of the brain and play a substantial role in neuroinflammation, bind to the Aβ peptide to help clear it from the brain (Yeh et al., 2017). APOE4 and TREM2*R47H are two crucial genetic risk factors in the late-onset sporadic AD population (Le Guen et al., 2022; Guerreiro et al., 2013; Jonsson et al., 2013). These genetic variants contribute to impaired uptake of Aβ and the subsequent accumulation of Aβ (Yeh et al., 2017), a critical molecule involved in the initiation of neuronal degeneration (Leng & Edison, 2021). The accumulation of Aβ activates the phagocytic function of microglia to degrade Aβ and triggers pro-inflammatory pathways (Leng & Edison, 2021). Moreover, activated microglia release reactive oxygen species and pro-inflammatory cytokines, leading to neuronal dysfunction and progressive cell death as the disease advances (Alawieyah Syed Mortadza et al., 2018; Combs et al., 2001).

Multiple phase 3 human clinical trials targeting Aβ in early-stage AD patients (mild cognitive impairment or mild dementia due to AD) have been conducted around the world; however, showing discouraging results with respect to Bapineuzumab (a humanized anti-amyloid-beta monoclonal antibody) (Salloway et al., 2014), Lecanemab (a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils) (van Dyck et al., 2023), Aducanumab (a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta) (Budd Haeberlein et al., 2022), Crenezumab (a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers) (Ostrowitzki et al., 2022), Gantenerumab (a fully human monoclonal antibody that binds aggregated Aβ and removes Aβ plaques by Fc receptor-mediated phagocytosis) (Ostrowitzki et al., 2017), and Solanezumab (a humanized monoclonal antibody, preferentially binds soluble forms of amyloid) (Doody et al., 2014; Honig et al., 2018).

The US FDA's recent accelerated approval of two anti-amyloid antibodies for the treatment of AD, aducanumab, and lecanemab, has caused substantial debate (Høilund-Carlsen et al., 2023). In particular, Lecanemab received accelerated approval from the FDA in July 2023 to treat early-stage AD patients; it reduced markers of amyloid and resulted in moderately less decline in measures of cognition and function than placebo at 18 months but was associated with adverse events such as amyloid-related imaging abnormalities (ARIAs) (van Dyck et al., 2023; Kurkinen, 2023). However, it was a rather disappointing step taken by the FDA because, in this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men, that is, there are two times more women than men living with AD. Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with two APOE4 genes. This is bad news for AD patients, 60%–75% of whom carry at least one APOE4 gene (Kurkinen, 2023). Experts also argued that the decreased amyloid PET signal in these trials using aducanumab and lecanemab is unlikely to be a one-to-one reflection of amyloid removal but rather a reflection of increased therapy-related brain damage, as supported by the increased incidence of ARIAs and reported loss of brain volume (Høilund-Carlsen et al., 2023). Therefore, they recommend that the FDA prioritize FDG PET, detection of ARIAs and accelerated brain volume loss with MRI in all trial patients, and neuropathological examination of all patients who die in these phase 4 trials (Høilund-Carlsen et al., 2023).

On October 24, 2023, the US FDA cleared an investigational new drug (IND) application for SNK01 natural killer (NK) cell therapy for the treatment of moderate AD (Biotech, 2023). SNK01 is ex vivo activated and expanded NK cell therapy. In phase I, 3 + 3 dose-escalation trial, data on the use of SNK01 to treat patients with AD demonstrated that SNK01 was well tolerated and appeared to cross the blood–brain barrier to help reduce proteins and neuroinflammation in a dose-dependent manner without any related serious adverse effects observed. No dose-limiting toxicities were reported, while positive changes in cognitive function and cerebrospinal fluid biomarkers were observed. A recent study suggests that mesenchymal stem cells could be considered a promising candidate for further exploration in cell-based therapy for AD (Farahzadi et al., 2020). This potential could be further investigated, especially in combination with NK cells, as a potential approach for treating AD.

However, how NK influences AD pathology and progression has not been fully investigated. Only a few studies were published on this topic. For example, one study investigates the expressions of dopamine D (Drummond & Wisniewski, 2017) and D (Yeh et al., 2017), as well as serotonin receptors, 5-HT(1A), 5-HT(2A), 5-HT(2B), and 5-HT(2C) in peripheral blood mononuclear cells (PBMCs) from AD patients and age and gender-matched control subjects (Martins et al., 2012). The results showed no significant differences among the study groups concerning the frequency of the immune cell sub-types (CD4⁺ T cells, CD8⁺ T cells, CD19⁺ B cells, CD14⁺ monocytes, and CD56⁺ NK cells). However, a significant increase in 5-HT(2C) exclusively in NK cells was observed in AD patients.

Does 5-HT(2C) have any impact on Aβ in the brain? A study of guinea pigs pointed to a possible mechanism. Chronic administration of mCPP (1-(m-chlorophenyl)piperazine) (2 mg/kg bid, i.p.), a 5-HT(2B/2C) agonist, increased cerebrospinal fluid (CSF) APP(s) levels when measured 2 h after the drug administration; hippocampal and cortical APP(h) levels were unaffected. However, mCPP also caused a significant decrease in body weight gain in guinea pigs (Arjona et al., 2002). These data suggest that the pharmacological activation of 5-HT(2C) can stimulate CSF APP(s) secretion and reduce Aβ production in vivo. Hence 5-HT(2C), which apparently is localized to the brain, may represent valuable targets for developing treatments for AD.

In addition to 5-HT(2C), the diversity of NK cells from patients with AD and control subjects was assessed using web-based single-cell RNA sequencing data of blood NK cells (Qi et al., 2022). This study identified a contraction of the NK cell compartment in AD, accompanied by a reduction of cytotoxicity. Unbiased clustering revealed four subsets of NK cells in AD, that is, CD56bright NK cells, CD56dim effector NK cells, adaptive NK cells, and a unique NK cell subset that is expanded and characterized by upregulation of CX3CR1, TBX21, MYOM2, DUSP1, and ZFP36L2, and negatively correlated with cognitive function in AD patients. Pseudo-temporal analysis revealed that this unique NK cell subset was at a late stage of NK cell development and enriched with transcription factors TBX21, NFATC2, and SMAD3.

Although several studies have shown that increased fruit and vegetable consumption did not affect NK cell populations in healthy human subjects (Heinz et al., 2010; Watzl et al., 2005), our studies showed that black raspberries enhance natural killer cell infiltration into the colon and suppress the progression of colorectal cancer (Pan et al., 2017) by targeting Smad4 in both colonic epithelium and NK cells (Huang et al., 2020). Consumption of soy isoflavone-enriched bread in men with prostate cancer is associated with increased circulating NK cells (Lesinski et al., 2015). This selectivity is likely because cancer patients have dysregulated signaling pathways in NK cells compared to healthy subjects, and phytochemicals correct these pathways, ultimately leading to the rescue of the NK cell functions. Notably, a diet rich in fruits and vegetables has demonstrated protective effects against cognitive decline and the onset of dementia in older adults (Zhou et al., 2022). The consumption of specific types of fruits and vegetables, including berries, soybeans, bean products, dark green leafy vegetables, nuts, cruciferous vegetables, root vegetables, fungi, and nuts, may reduce the risk of cognitive disorders. Moreover, these protective effects are particularly noteworthy in the Chinese population, where the traditional Chinese diet pattern is characterized by whole grains, tea, soybeans, and vegetables, along with a high content of phytochemicals such as catechol and caffeine. Given the potential of fruits and vegetables in regulating NK cells, how they impact cognitive decline by affecting NK cell-based therapies in AD patients warrants further investigation.