NOD2 in Alzheimer’s Diseases: Comparison
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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by a progressive decline in cognitive function, including memory loss, language difficulties, and changes in behavior. Researchers have demonstrated the potential of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor agonists in AD treatment. These agonists facilitate the conversation of pro-inflammatory monocytes into patrolling monocytes, leading to the efficient clearance of amyloid-β (Aβ) in the AD-affected cerebrovascular system. This approach surpasses the efficacy of targeting Aβ formation, marking a significant shift in therapeutic strategies. 

  • Alzheimer’s diseases
  • NOD2
  • MDP
  • monocyte

1. Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by a progressive decline in cognitive function, including memory loss, language difficulties, and changes in behavior. Despite extensive research efforts, AD continues to pose a significant global health burden, with over 50 million cases of dementia worldwide, estimated to rise to over 152 million cases by 2050, and AD accounting for 60–70% of all cases according to the World Health Organization. Furthermore, AD is a leading cause of death worldwide, with a mortality rate of 6.6% per year, and it was the sixth leading cause of death in the United States in 2017. Although the exact etiology of AD remains unclear, certain risk factors have been linked to its onset, including aging, genetics, and lifestyle factors. Aging is the most significant risk factor, with the risk of AD doubling every five years after the age of 65 [1]. Genetics also play a crucial role, with mutations in genes such as APP, PSEN1, and PSEN2 elevating the risk of AD [2]. Furthermore, lifestyle factors, such as diet, physical activity, and social engagement, have been found to be involved in the development of AD [3].
Over the past decades, various theories have been proposed in order to better understand the etiology of AD. The tau hypothesis and the amyloid deposition hypothesis are two well-known theories that elucidate underlying pathogenic mechanisms and may affect treatment options. The tau hypothesis suggests that tau protein is a key component in the maintenance of microtubules, which are essential for neuronal structure and function. Its segregation from microtubules and the development of neurofibrillary tangles is due to tau phosphorylation in AD. This condition, which affects axon transport and neuronal function, leads to the development of cognitive decline in people with AD. On the other hand, the amyloid deposition theory is based on the accumulation of beta-amyloid peptide (Aβ) in senile plaques, which disrupt nerve signaling and induce inflammation, which ultimately leads to neurodegeneration and cognitive decline. BACE1 and the γ-secretase complex are two of the enzymes that degrade amyloid precursor protein (APP) to produce Aβ1-42 (Aβ42), which is the more toxic variant, and Aβ1-40 (Aβ40). Studies have found an association between amyloid deposition and tau hyperphosphorylation, indicating that Aβ synthesis and deposition precede and contribute to tau pathology. The importance of the degree of cognitive decline in the progression of AD is emphasized by the level of oligomeric form of Aβ. Familial AD accounts for approximately 4–6% of cases with an overt genetic predisposition, lending further credence to the amyloid hypothesis. Mutations in the APP, PS1, and PS2 genes are associated with early-onset AD. Mutations in the apolipoprotein E4 (APOE4) gene have been shown to be an important risk factor for late-onset hereditary AD. The amyloid hypothesis is further supported by the fact that these mutations promote amyloid accumulation [4].
Current therapeutic approaches for AD are focused on slowing the progression of the disease and alleviating its symptoms, as a definitive cure remains elusive. Non-pharmacological interventions, such as cognitive training and physical exercise, have also been shown to be effective in enhancing cognitive function and delaying the onset of dementia. Moreover, targeting systemic innate immune cells, such as monocytes and macrophages, has emerged as a potential therapeutic avenue for AD [5]. Monocytes are a type of white blood cell that play important roles in the innate immune response and are generated in the bone marrow from hematopoietic stem cells and differentiate into distinct subsets based on the expression of specific cell surface markers. However, there are some differences in the markers that are expressed on monocytes in mice and humans. For example, in mice, the main subsets of monocytes are Ly6Chigh (equivalent to human classical/inflammatory monocyte) and Ly6Clow (equivalent to human non-classical/patrolling monocyte), whereas in humans, the main subsets are CD14++CD16− (classical) and CD14+CD16+ (non-classical) monocytes. Once the monocytes are generated, they need to exit from bone marrow and carucate in blood to migrate to tissues into macrophages. In terms of markers involved in monocyte migration, CCR2 is important for the migration of both monocytes from the bone marrow to the bloodstream and to sites of inflammation. Markers involved in monocyte differentiation and activation, such as NF-kB, NR4A1, and NOD2, are also expressed on both human and mouse monocytes. However, there may be some differences in the specific signaling pathways and downstream effects of these markers in mice and humans. The proliferation, differentiation, and migration of monocytes has been already reviewed in researchers previously published paper [6].
Over the last decade, the studies of researchers laboratory uncovered the crucial role of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the function of monocytes. Indeed, researchers showed the activation of NOD2 receptors in the function of monocytes as a key switch for monocyte conversation from classical to patrolling monocytes in murine models of AD [6[6][7],7], as well as autoimmune diseases of multiple sclerosis (MS) [8], which contribute to the clearance of toxic amyloid beta (also known as Aβ), a hallmark of AD, and myelin debris in MS. The switch of monocyte conversation from classical to patrolling monocytes in response to NOD2 signaling was shown to play a powerful beneficial role in engulfing the toxic Aβ from the luminal side of the cerebrovascular system, which finally leads to improvement in AD symptoms.

2. NOD2 in Alzheimer’s Diseases

NOD2 receptors are a type of receptor that is involved in the body’s innate immune response. They are located within certain immune cells and their main function is to recognize and respond to bacterial peptidoglycan (PGN) fragments, which are typically found in bacterial cell walls. This recognition leads to the activation of signaling proteins, which stimulate the production of pro-inflammatory cytokines and other immune mediators that help to fight off bacterial infections. NOD2 receptors also play a role in autophagy, a cellular process that helps to break down and recycle components of the cell. NOD2 receptors are expressed in various immune cells, including bone marrow cells and monocytes [9]. Bone marrow cells, which are progenitor cells for all blood cells, express NOD2 receptors at various stages of their differentiation. Studies have shown that NOD2 signaling plays a role in the differentiation of bone marrow cells into monocytes and dendritic cells, two types of immune cells that play a critical role in the innate immune response [10].
Researchers previous studies showed that activation of NOD2 by muramyl dipeptide (MDP), a small molecule that is derived from PGN, converts inflammatory monocytes into patrolling monocytes, which have a greater ability to phagocytose and clear vascular amyloid associated with AD [10]. Patrolling monocytes are a subpopulation of monocytes that circulate in the bloodstream and are capable of migrating to various tissues to perform immune surveillance functions. Recent studies have shown that patrolling monocytes have a greater ability to phagocytose compared to classic monocytes or brain residential microglia. One study conducted by Auffray et al. (2009) showed that patrolling monocytes were more effective at phagocytosing apoptotic cells than other monocyte subsets. Indeed, they found that patrolling monocytes expressed higher levels of the scavenger receptor CD163, which is known to play a role in phagocytosis of apoptotic cells [11]. Another study by Grabert et al. (2016) investigated the role of patrolling monocytes in the phagocytosis of Aβ. They demonstrated that patrolling monocytes were the primary phagocytic cells responsible for clearing Aβ from the brain, suggesting that these cells may play an important role in the pathogenesis of AD [12]. These studies were recently reviewed by us [6]. Taken together, these studies suggest that patrolling monocytes have a unique ability to phagocytose cellular debris and foreign material in a variety of tissues, including the brain vascular system. This may have important implications for the development of new therapies for diseases that involve excessive accumulation of toxic proteins and cellular debris, such as AD and MS, respectively.
The conversation of monocyte subsets seems to be dependent on NR4A1 (also named Nur77), a transcription factor that plays a crucial role in the production of patrolling monocytes [13]. The recruitment of patrolling monocytes to vascular amyloid deposits is still not fully understood, but it is believed that CCR2, CCR5, and CX3CR1 each are partially involved in their recruitment [14,15][14][15]. Additionally, the intravital two-photon microscopy of researchers laboratory has demonstrated that patrolling monocytes are specifically attracted to the luminal wall of Aβ-positive vasculatures, and their removal has been shown to lead to a significant decrease in Aβ plaques [6]. This suggests that increasing the number of patrolling monocytes in the vasculature could be a potential therapeutic avenue for AD. The mechanism of Aβ efflux from the brain to the vasculature, called the sink effect, is also being explored as a potential avenue for AD therapy [6].
The previous studies of the laboratory uncovered a high potential of the NOD2 ligand, MDP in monocyte conversation, and pathophysiology of AD in its animal models. Indeed, researchers showed that MDP triggers the conversion of inflammatory monocytes (Ly6Chigh) into patrolling monocytes (Ly6Clow) in an NOD2-dependent manner. Indeed, mice injected with MDP had a strong increase in the number of patrolling monocytes associated with a decrease in inflammatory monocytes. However, when NOD2−/− mice were injected with MDP, no switch was observed, indicating that MDP triggers the conversion in an NOD2-dependent manner. The results also showed that MDP has a powerful impact on the short-term memory of APP mice, an excellent model of AD for studying the amyloidopathy, since mice display cognitive impairment at 6 months of age. The principal manifestation of this decline is short-term memory loss and cerebral amyloid angiopathy [10,16][10][16]. In another study, researchers also found that MDP-stimulated NOD2 was associated with the increased expression of the Aβ transporter, the low-density lipoprotein receptor-related protein-1 (LRP-1). LRP-1 transports Aβ from the abluminal to luminal side of the blood brain barrier (BBB) where patrolling monocytes can scavenge it [6]. In sum up, using the potential of patrolling monocytes for engulfing cerebrovascular Aβ instead of using approaches that target Aβ plaque formation was found to be a better strategy in AD treatment.
As an auxiliary elucidation to enhance the portrayal of researchers methodology in scrutinizing the behavior of monocytes in Aβ elimination from the brain and cerebrovascular system, researchers deemed it beneficial to elucidate that researchers employed chimeric mice in researchers study to distinguish between brain-resident microglia and bone-marrow-derived (peripheral) macrophages within the CNS. Adult APP mice, serving as models of AD, had their bone marrow (BM) hematopoietic cells supplanted with green fluorescent protein (GFP)-expressing cells, facilitating the identification of infiltrating monocytes or bone-derived macrophages via the presence of GFP. In contrast, GFP-negative macrophages were identified as microglial cells that had differentiated into macrophages. The BM utilized for this purpose was procured from sex-matched CX3CR1-GFP donors and transplanted into adult male APP recipient mice. These recipient mice had their BM hematopoietic cells previously eradicated through chemotherapy. Approximately 8 weeks post-transplantation, to authenticate the successful chimerism, researchers evaluated peripheral blood samples via Fluorescence Activated Cell Sorting (FACS) to quantify the number of donor-derived cells in the recipient mice [16].
In the context of Aβ removal from the cerebrovascular system, researchers employed the APP mouse model to scrutinize the activity of monocytes within the vasculature. Aβ was stained with Congo red, which was injected into the cerebral spinal fluid via the cisterna magna, prior to imaging sessions. Immediately before imaging, Qdot 705 was administered via the tail vein to label the blood vessels. Given that researchers had generated chimeric mice in which the APP mice’s BM was replaced with GFP-tagged CX3CR1 cells, researchers were able to monitor the monocyte behavior inside the vessels using in vivo imaging [16].

References

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  3. Dhana, K.; Evans, D.A.; Rajan, K.B.; Bennett, D.A.; Morris, M.C. Healthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studies. Neurology 2020, 95, e374–e383.
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  6. Piec, P.A.; Pons, V.; Préfontaine, P.; Rivest, S. Muramyl Dipeptide Administration Delays Alzheimer’s Disease Physiopathology via NOD2 Receptors. Cells 2022, 11, 2241.
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  9. Negroni, A.; Pierdomenico, M.; Cucchiara, S.; Stronati, L. NOD2 and inflammation: Current insights. J. Inflamm. Res. 2018, 11, 49–60.
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  11. Auffray, C.; Fogg, D.; Garfa, M.; Elain, G.; Join-Lambert, O.; Kayal, S.; Sarnacki, S.; Cumano, A.; Lauvau, G.; Geissmann, F.; et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007, 317, 666–670.
  12. Grabert, K.; Michoel, T.; Karavolos, M.H.; Clohisey, S.; Baillie, J.K.; Stevens, M.P.; Freeman, T.C.; Summers, K.M.; McColl, B.W. Microglial brain region−dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 2016, 19, 504–516.
  13. Hanna, R.N.; Carlin, L.M.; Hubbeling, H.G.; Nackiewicz, D.; Green, A.M.; Punt, J.A.; Geissmann, F.; Hedrick, C.C. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6—Monocytes. Nat. Immunol. 2011, 12, 778–785.
  14. Thomas, G.; Tacke, R.; Hedrick, C.C.; Hanna, R.N. Nonclassical Patrolling Monocyte Function in the Vasculature. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1306–1316.
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