Function of Nogo‐A/Nogo‐A Receptor in Alzheimer's Disease

Summary

Nogo‐A is a protein inhibiting axonal regeneration, which is considered a major obstacle to nerve regeneration after injury in mammals. Rapid progress has been achieved in new physiopathological function of Nogo‐A in Alzheimer's disease in the past decade. Recent research shows that through binding to Nogo‐A receptor, Nogo‐A plays an important role in Alzheimer's disease (AD) pathogenesis. Particularly, Nogo‐A/Nogo‐A receptors modulate the generation of amyloid β‐protein (Aβ), which is thought to be a major cause of AD. This review describes the recent development of Nogo‐A, Nogo‐A receptor, and downstream signaling involved in AD and pharmacological basis of therapeutic drugs. We concluded the Nogo‐A/Nogo‐A receptor provide new insight into potential mechanisms and promising therapy strategies in AD.

Introduction

Alzheimer's disease (AD) is a prevalent neurodegenerative disease that progressively impairs the memory and cognition of patients 1 and is particularly common in the elderly. The main pathological changes are senile plaques (SP) caused by accumulation of Aβ and neurofibrillary tangles formed by hyperphosphorylated tau 2. Until now, the causes of AD have not been completely clear. Age is a major contributing factor due to the fact that the prevalence of AD in patients above 65 grows exponentially. According to studies on patients with familial AD, there are three genes that are mutated in these patients, namely amyloid β‐protein precursor (APP), presenilin 1 (PS1), and presenilin 2 (PS2) 3. However, patients with familial AD only account for a small number of cases, the majority of patients with AD arise from sporadic onset 4, neither have family history or a Mendelian distribution, nor are related to the diversity of the apolipoprotein E (ApoE4) gene 5. Mutation in the APP and PS genes leads to excessive Aβ generation, whereas changes in the ApoE4 gene results in altered clearance and transport of Aβ, which may contribute to amyloid plaque deposition and accelerate the progression of AD 6.

Although research on AD pathogenesis has made substantial progress, the exact etiology is not well understood. To date, there are many hypotheses to explain the pathogenesis of AD, including the amyloid, tau hyperphosphorylation, oxidative stress and excitotoxicity, and inflammation hypotheses, of which the amyloid hypothesis is the most accepted. The 40‐residue Aβ peptide (Aβ ₄₀) and 42‐residue Aβ peptide (Aβ ₄₂) are the two major forms of Aβ monomers. The highly amyloidogenic Aβ ₄₂ is more prone to aggregate and more neurotoxic than the shorter Aβ species. They are generated from cleavage of APP by β‐secretase and γ‐secretase. In light of the amyloid hypothesis, overproduction and accumulation of Aβ trigger the onset and accelerate the development of AD 7.

Despite the substantial progress on studying AD pathogenesis, an effective treatment to delay the onset and progression of AD has not been developed. There is an urgent need to research the pathogenesis of AD and identify a novel target for drug intervention. Recent studies suggest that the Nogo‐A/Nogo‐A receptor plays an essential role in the progression of AD, affecting neurodegeneration as well as Aβ metabolism. Consequently, interventions directed at this target may not only promote neuroregeneration and restore the neural network, but may also reduce the generation of Aβ, playing dual roles in treating AD. This review will summarize recent advances in Nogo‐A/Nogo‐A receptor research in AD and aim at providing new ideas for AD pathogenesis and drug intervention.

Discovery of Nogo‐A/Nogo‐A Receptor

Nogo‐A is a myelin protein with a molecular mass of 256 KDa, composed of 1192 amino acids, and is encoded by the Nogo gene. Nogo‐A was found to inhibit neurite outgrowth in dorsal root ganglion cells 7, 8, PC12 cells 7, and cerebellar granule cells 9, which is considered a major obstacle to nerve regeneration after injury in adult mammalian CNS. Later it was discovered that Nogo‐A belonged to a larger reticulon protein family (RTN). To distinguish it from the other three types of RTNs 10, Nogo is also called RTN 4 and Nogo‐A is called RTN4A, respectively. Nogo‐A has a short C‐terminal tail, an extracellular N‐terminus, and two transmembrane domains. Fragment analyses and binding studies showed that Nogo‐A contains more than one growth inhibiting domain, and two principal domains of Nogo‐A have been shown to induce growth cone collapse and exert inhibitory effects on neurite outgrowth: the Nogo‐66 loop (1055‐1120 amino acid residues, located between two hydrophobic domains) and Nogo‐A‐Δ20 (544‐725 amino acid residues, part of “Amino‐Nogo”) 11, 12.

Fournie et al. 13 first discovered the existence of the Nogo‐66 receptor (NgR), which specifically bound to Nogo‐66 domain. Afterward several homologous NgRs were consecutively found and the one binding to Nogo‐66 was renamed NgR1, a glycophosphatidylinositol‐anchored protein (GPI) with a plurality of leucine‐rich repeat (LRR) structures. In addition to Nogo‐66, two other myelin‐associated inhibitors (MAIs), myelin‐associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) 14, can bind to NgR1 and limit axon regeneration and sprouting in the injured brain. Moreover, a novel receptor for Nogo‐66, paired immunoglobulin‐like receptor B (PirB), was recently discovered, and it plays a role similar to NgR1 15.

To transduce intracellular signals, NgR1 forms a receptor complex including the membrane proteins p75 neurotrophin receptor (p75NTR) and/or a TNF receptor family member TROY, the LRR‐protein LINGO‐1 and converge on the activation of RhoA, leading to growth inhibition via the rho‐associated coiled coil‐containing protein kinase (ROCK) 16. Activation of the RhoA/ROCK pathway results in actin depolymerization via the regulation of LIM kinase (LIMK) and cofilin, increased actomyosin contraction via regulation of the myosin light chain II (MLC II) and disassembled microtubule via the collapsin response mediator protein 2 (CRMP2) 16. Furthermore, the combination of Nogo‐66 and receptor inhibits the activation of phosphorylated protein kinase B (PKB) and glycogen synthase kinase 3β (GSK3β) 17, 18. The CRMP‐4 is a major target of GSK‐3β in controlling cytoskeleton dynamics and has the ability to complex with RhoA 19, 20. Other signaling components of Nogo‐A include protein kinase C (PKC) and epidermal growth factor receptor (EGFR), whereby pharmacological blockade of PKC α/β and EGFR was shown to decrease Nogo‐66 and myelin‐mediated growth inhibition 21, 22.

Apart from Nogo‐66, Nogo‐A‐Δ20 is another extracellular domain in the N‐terminal region of Nogo‐A (Amino‐Nogo), which regulates axonal regeneration 11. Although Hu and Strittmatter 23 revealed that some integrins, such as ɑ_v and ɑ₅, are sensitive to Nogo‐A and are involved in the inhibition of axonal outgrowth mediated by Amino‐Nogo, its mechanism had been unclear until very recently. Kembf et al. 24 discovered that the sphingosine 1‐phosphate receptor 2 (S1PR2) had been identified as a specific receptor and signal transducer for the Nogo‐A‐Δ20. The S1PR2 is one kind of G‐protein‐coupled receptor, which contains 7‐transmembrane domain and belongs to the subfamily of S1PR. The S1PR family is thought to be activated by the low‐molecular‐weight lipid ligand sphingosine 1‐phosphate (S1P), which exerts diverse receptor‐specific effects on various cell types including regulation of apoptosis, cell motility, and cytoskeleton dynamics 25. Nogo‐A‐Δ20 binding to S1PR2 activates the G‐protein G‐13, the leukemia‐associated Rho guanine exchange factor (RhoGEF) LARG and RhoA, which induce the inhibition of neurite growth or fibroblast spreading 24. On the other hand, Nogo‐A‐Δ20 could upregulate the expression levels of the RhoA and downregulate the levels of phosphor‐cyclic AMP response element‐binding (p‐CREB) in dorsal root ganglion cells 26. It has been identified that Akt acts is a novel signaling component of the amino‐Nogo pathway and the activation of Akt blocks the inhibitory effects of amino‐Nogo 27.

Nogo‐A plays a pivotal role in the prevention of axonal regeneration after central nervous system (CNS) injury in mammals, which has been extensively studied in the field of spinal cord trauma, ischemic stroke, optic nerve injury, and models of multiple sclerosis 12. The interaction of Nogo‐A with its different receptors (NgR1, S1PR2, and PirB) restricts plasticity and neurite growth via the activation of different signaling pathways 28. Additionally, recent studies have suggested that Nogo‐A signaling plays novel important roles in the repression of synaptic plasticity in mature neuronal networks of the CNS, which extend our understanding of Nogo‐A's function far beyond its well‐studied role as axonal‐growth inhibitor 29, 30, 31, 32. Here, this review will describe recent developments in the study of Nogo‐A/Nogo‐A receptor and signaling in AD and the pharmacological basis of therapeutic drugs.

The Distribution of Nogo‐A and Nogo‐A Receptor in AD Brain

The distributions of Nogo‐A and NgR1 have been reported using in situ hybridization in the rat CNS. Nogo‐A is abundantly expressed in both neurons and oligodendrocytes throughout the central nervous system, particularly with high levels of Nogo‐A expression in the olfactory bulb, pyramidal cells and interneurons in the hippocampus, spinal motor neurons, and dorsal root ganglion cells 33, 34. In contrast, NgR1 mRNA expression is very restricted and has been found to be expressed in the neocortex, hippocampus, and amygdala in human brain 33.

The PirB is expressed in a variety of hematopoietic cells, which include B cells, mast cells, macrophages, granulocytes, and dendritic cells 35. Recent studies have demonstrated that PirB is also expressed in regions of the CNS, including the cerebral cortex, hippocampus, cerebellum, and olfactory bulb but not in the adult spinal cord 36. PirB is expressed at low or undetectable levels, although its expression may be more prominent during neural development or after ischemia 37. In addition, PirB expression in the hippocampus and cortex significantly increased following treatment with lipopolysaccharide, which is a strong inducer of innate immunity and chronic inflammation in CNS 38.

The S1PR2 express widely in immune, nervous, metabolic, cardiovascular, musculoskeletal, and renal systems and the bioactive S1PR2 involved in cell proliferation, angiogenesis, inflammation, and malignant transformation 25. Situ hybridization revealed exclusive S1PR2 expression in the hippocampal pyramidal/granular neurons of wild‐type mice. The immunohistochemistry/microarray analyses identified enhanced gliosis in the whole hippocampus and neighboring neocortex in seizure‐prone S1P2^−/− mice 39.

Gil et al. 40 provided evidence that Nogo‐A is overexpressed by hippocampal neurons and is associated with Aβ deposits in SP as determined by immunohistochemistry in patients with AD. The ratio of NgR1‐immunopositive neurons to the total number of neurons is significantly higher in the CA1 and CA2 subfields of the human AD hippocampus than that in normal aging hippocampus 41. Furthermore, Park and Strittmatter 42 reported that the distribution of Nogo and NgR1 differs in the brain sections of patients with AD. Specifically, NgR1 centralizes in the neuron cell body and a fraction of NgR1 protein is also concentrated in amyloid plaques in the normal aging group, whereas Nogo‐A shifts to the neuronal perikarya in all of AD cases. The distribution of other two receptors PirB and S1PR2 in patient with AD remains unclear.

Role of Nogo‐A in AD

In the past decade, research has shown that Nogo‐A plays an essential role in neurodegeneration. It was first discovered that there were four members in the reticulon family, including RTN1, RTN2, RTN3, and RTN4‐B, all of which were binding partners of the beta‐site APP cleaving enzyme 1 (BACE1 or β‐secretase) 43. In addition, an increase in the expression of any reticulon protein substantially reduces the production of Aβ in HEK‐293 cells, while lowering the expression of RTN3 by RNA interference increases the secretion of Aβ 44. It has been shown that RTNs interact with BACE1 and negatively modulate its processing of APP at the β‐secretase site and overexpression of RTN3 in neurons has reduced amyloid deposition and RTN3 deficiency facilitates amyloid deposition 45, 46, 47. Besides, Transgenic mice overexpressing RTN3 are accumulated in a distinct population of dystrophic neurites 48 and the presence of dystrophic neurites impairs cognition in AD brain.

RTN3 appears to regulate the formation of both amyloid deposition via negative modulation of BACE1 activity and dystrophic neurites via the formation of RTN3 aggregates 49. Blocking abnormal RTN3 aggregation is therefore a promising therapeutic strategy for enhancing cognitive function of patients with AD.

Moreover, Maslish et al. 50 reported, deleting Nogo‐A ameliorated learning and memory deficits of APP transgenic mice and decreased AD related pathology. It is hypothesized that the overexpression of Nogo‐A and activation of NgR1 inhibit neurite outgrowth and alter neuronal metabolism, resulting in overproduction of Aβ ₄₂ 51.

Recently, studies show that Nogo‐A could serve as an crucial negative regulator of synaptic plasticity and cognitive function 29, 32. Studies of long‐term potentiation (LTP) in hippocampal slice demonstrated that administration of soluble Nogo‐66 or OMgp altered synaptic plasticity, suppressing LTP and enhancing long‐term depression (LTD) 12. Acute neutralization of endogenous Nogo‐A or NgR1 or knockdown of Nogo‐A increased LTP in vivo. Interestingly, it has been suggested that synaptic activity is one of the most important factors that regulate Aβ levels, facilitates APP internalization and cleavage 6. However, there is hardly researches to report the relationship between the novel roles of Nogo‐A played in synaptic plasticity and the pathogenesis of AD. Thus, data support the view that Nogo‐A triggers the onset and development of AD via influencing the metabolism of Aβ and probably restricting synaptic plasticity.

Role of Nogo‐A Receptor in AD

NgR1 was the first Nogo‐A receptor discovered with a signaling pathway that played an important role in inhibiting axon regeneration. The NgR‐mediated response to myelin inhibitors is known to participate in restricting axonal and synaptic plasticity 52. Thus, brain myelin proteins impede both physiological plasticity and the repair of pathological injury by a shared NgR mechanism. NgR1 might be involved in the pathological process of AD by affecting the metabolism of APP 42.

Park et al. 53 highlighted that overexpression of NgR decreased Aβ production in neuroblastoma culture. As their experiments in transfected cells showed, NgR1 interacted with APP in the domain of Aβ. Importantly, the binding capacity varied depend on the length of Aβ, and they demonstrated that the central 15–28 aa of Aβ associated with specific surface‐accessible patches on the leucine‐rich repeat concave side of the solenoid structure of NgR, different from binding zone of Nogo‐66.

To explore whether the interaction between NgR and Aβ had physiological functions, researchers conducted in vivo experiments on mice. Previously, researchers 54 found that mice lacking NgR1 showed increased Aβ accumulation in the hippocampal dentate gyrus and cerebral cortex. Cerebroventricular administration of NgR (310) ecto‐Fc reduces levels of Aβ in the brain of APP swe/PSEN‐1ΔE9 mice, and there is a negative correlation between the level of Aβ, NgR1, and dystrophic neurites. They also found that subcutaneous injection of NgR (310) ecto‐Fc reduced brain Aβ deposition in APP swe/PSEN‐1ΔE9 transgenic mice and improved short‐term memory. NgR1 functions as a peripheral sink for Aβ, contributing to the clearance of peripheral Aβ, resulting in decreased accumulation in the brain and improved in transgenic mice. The possibility of side effects is also reduced due to the fact that NgR1 cannot cross the blood brain barrier (BBB). Therefore, it is likely that the peripheral association of NgR (310) ecto‐Fc with central Aβ residues provides an effective therapeutic approach for AD.

Zhou et al. 55 proposed that a family of proteins named Nogo receptor proteins (NgR1 to NgR3) regulated production of Aβ via interaction with APP. Further mapping of the interacting domain indicates that a small region adjacent to the BACE1 cleavage site of APP mediates the interaction of APP with NgR. These results suggested that increased interaction between Nogo receptor and APP reduces surface expression of APP and favors processing of APP by BACE1.

In addition to these myelin‐associated inhibitors (MAIs), other ligands for NgR1 have been discovered. For instance, B‐lymphocyte stimulator (BlyS) is a negative regulator of neuronal functions. NgR1 is identified as a high‐affinity receptor for BLyS, which inhibits dorsal root ganglion outgrowth in vitro 56. It has been found 57 that cartilage acidic protein‐1b as a endogenous NgR antagonist that competes with Nogo for binding to NgR1 and highlights the complex regulation of Nogo‐A and NgR1 function in vivo. The study shows that NgR1 and NgR3, but not NgR2 also bind chondroitin sulfate proteoglycans (CSPGs) using double and triple KO mice of NgR1, NgR2, and NgR3 58. Another ligand is the leucine‐rich glioma inactivated protein (LGI), which competitively binds to NgR1 and Nogo‐66 59. Disintegrin and metalloproteinase domain‐containing protein 22 (ADAM22) serves as a receptor for LGI, binds to NgR1, and forms a stable complex 60, playing a role in synaptic maturation and dendrite formation. Additional research suggested that downregulation of LGI3 clearly inhibited Aβ uptake by cultured rat astrocytes and LGI3 is involved in Aβ uptake by astrocytes through endocytosis 61.

In 2008, researchers identified another receptor for the three mentioned myelin‐associated inhibitors (MAIs), paired immunoglobulin‐like receptor B (PirB), which is structurally unrelated to the NgRs but is able to bind to and mediate the growth inhibitory effects of Nogo‐A, MAG, and OMgp 15. In studies of the activation of the PirB pathway in axon outgrowth inhibition, Taylor et al. 62 reported that the scaffold protein Plenty of SH3s (POSH) could limit axon growth through a Shroom3‐ROCK‐myosin signaling pathway. Dickson et al. 63 found that POSH, which is an intracellular signal transducer, in association with Shroom3 and the mixed lineage kinase (LZK), relays axon outgrowth inhibition downstream of Nogo‐66 and PirB. It has been suggested that a POSH‐dependent mechanism operates to inhibit axon outgrowth in different types of CNS neurons. To confirm the function of PirB, Omoto et al. 64 performed experiments on PirB gene‐knockout mice and found that the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB‐knockout mice, suggesting that blocking the function of PirB is not sufficient to promote axonal regeneration or functional recovery after cortical injury. However, evidence for a role of PirB in spinal cord regeneration is sparse in vivo 65. Recently, Kim et al. 66 demonstrated that murine PirB and its human homology leukocyte immunoglobulin‐like receptor B2 (LilrB2), which is present in human brain, are receptors for Aβ oligomers with nanomolar affinity. Compared to Aβ monomer, Aβ oligomers have a higher binding affinity for PirB. It has also been reported that the deleterious effect of Aβ oligomers on hippocampal long‐term potentiation required PirB in a transgenic model of AD. PirB contributes to not only to memory deficits in adult mice, but also to loss of synaptic plasticity in the juvenile visual cortex. These results imply that LilrB2 is responsible for human AD neuropathology and blocking the interaction between Aβ oligomers and LilrB2 may be a potential strategy for AD therapy.

In addition to the NgR1 and PirB, a crucial Nogo‐A receptor was discovered recently. Kempf et al. 24 firstly reported that the S1PR2 was recognized as a high‐affinity receptor for Nogo‐A‐Δ20 and Nogo‐A‐Δ20 bounding to S1PR2 extracellular domain loops2 and loops3, which is distinct from the proposed S1P binding pocket. It has been suggested that Nogo‐A‐Δ20 domain of Nogo‐A binds to S1PR2 and activates the signal transduction through the G‐protein G13, RhoGEF LARG and RhoA. Deleting or blocking S1PR2 counteracts Nogo‐A‐Δ20 and myelin‐mediated inhibition of neurite outgrowth and cell spreading, similar to previous results obtained by blocking Nogo‐A.

Alzheimer's disease is considered as a wide loss of synapses and deficits in spatial memory. The S1PR2 could be identified as an important regulator of synaptic stabilization in the adult CNS. The potential maintains high during the LTP when the S1PR2 had been pharmacologically blocked 24. Vitolo et al. 67 revealed that Aβ treatment of cultured hippocampal neurons leads to inhibition of LTP via inactivation of cAMP/PKA/CREB‐signaling pathway. The previous studies suggested that Nogo‐A‐Δ20 could induce a decreased levels of p‐CREB, which may aggravate the inhibition of LTP induced by Aβ 26.

It had been found that the migration of neural progenitor cells toward areas of brain infarction is significantly enhanced when S1PR2 blocked using a specific inhibitor JTE013 68. S1PR2 remarkably expresses in the hippocampus and augments extensive gliosis in this area through the study of S1PR2^−/− mice. These mice were also susceptible to lethal seizures and displayed impaired spatial working memory in the eight‐arm radial maze test and increased anxiety in the elevated plus maze test 39.

It has been well known that the NgR1 and PirB could combine with Aβ. It could be hypothesized that another Nogo‐A receptor S1PR2 binds to Aβ. However, there is no study on the correlation between S1PR2 and Aβ.

Downstream Signaling of Nogo‐A Receptor and AD

As we know, Nogo‐A exerts the inhibition effect of neuron regeneration and plasticity by binding to three different Nogo‐A receptors (NgR1, S1PR2, and PirB) via different signaling pathway 12, 28. But the RhoA/ROCK pathway is the common signaling pathway, and the activation of the RhoA/ROCK pathway results in a destabilization of the cytoskeleton affecting microtubules via CRMP2 and actin fibers via MLCII and Cofilin 16. Several reports have highlighted findings that RhoA/ROCK pathways are involved in the progression of AD.

The Rho‐ROCK pathway considered a key regulator of action cytoskeleton remodeling and dendritic spine maintenance 69. Rho‐ROCK pathway was also involved in AD by playing different roles including regulation of APP metabolism, inhibition of neuron regeneration, decreased level of phosphorylated tau and inactivation of glycogen synthase kinase 3β 69, 70, 71, 72.

Rho‐ROCK may be involved in the metabolism of APP, which affects the generation of Aβ. Several reports have shown that a subset of nonsteroidal antiinflammatory drugs (NSAIDs) could decrease the levels of Aβ both in vitro and in vivo 73, 74. But the mechanism of lowering Aβ production is controversial. Although the first study has demonstrated that NSAIDs directly modulates the γ‐secretase activity 75, another study suggested that NSAIDs reduce Aβ production because of inhibiting the RhoA/ROCK pathway 76. Recently, Fasudil as a Rho kinase inhibitor was shown to have beneficial effects on cognitive impairment and neuronal toxicity induced by Aβ 77.

Statins are also reported to reduce levels of Aβ by inhibiting the Rho‐ROCK pathway in vitro and in vivo 78. Inhibition of Rho‐ROCK results in activation of α‐secretase cleavage or the enhancement of APP lysosomal degradation, both of which lead to the reduction of Aβ production 79, 80, 81. It has been found that ROCK inhibitor Y‐27632 promotes neuron regeneration and reduces Aβ in cortical neurons 51. However, the exact mechanisms of how ROCK regulates APP processing are not well understood. Lane et al. 82 reported that ROCK formed complexes with the Vps10‐domain protein and sortilin‐related receptor (SorL1), Both ROCK inhibition and ROCK knockdown enhanced generation of both soluble APP and Aβ. Additionally, activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. These results highlighted the potential importance of SorL1 in elucidating the regulation of APP metabolism through ROCK and PKC.

With regard to the mechanism by which Aβ limits axon generation of SH‐SY5Y cells, Kubo 72 reported that inactivation of collapsin response mediator protein‐2 (CRMP‐2) via ROCK‐induced phosphorylation results in neurite outgrowth inhibition. Chacon et al. 83 found that inactivation of RhoA‐GTPase and activation of protein tyrosine phosphatase 1B (PTP1B) protect cultured hippocampal neurons against the noxious effects of Aβ. Heredia et al. 84 indicated that Aβ degeneration requires the activation of LIMK1 and the rearrangement of actin cytoskeleton. In addition, high levels of p‐LIMK1 were found in AD brain. Hamano 71 suggested that pitavastatin reduces total and phosphorylated tau levels in a cellular model of tauopathy via the inactivation of Rho/ROCK in primary neuronal cultures.

Recently, Qin et al. 85 supported that silent information regulator of transcription 1 (SIRT1) was involved in the cleavage of APP through the regulation of ROCK expression. Afterward, it was also demonstrated that Aβ _25‐35‐suppressed SIRT1 activity was significantly reversed by resveratrol via the ROCK downregulation. These results clearly revealed that resveratrol protected PC12 cells from Aβ‐induced cell apoptosis through regulation of SIRT1 and ROCK 86.

Huesa et al. 87 found a prominent RhoA mislocalization in patients with AD and in the Tg2576 mouse model. RhoA immunostaining decreased in the neuropil and markedly increased in the neurons of patients with AD, and decreased in synapses and increased in dystrophic neurite of Tg2576 mice. R‐Flurbiprofen (belong to NSAID) lowered the level of Aβ and improved learning and memory deficits in a transgenic animal model of AD 88. Musilli et al. 89 showed the Rho‐GTPase activator cytotoxic necrotizing factor 1 (CNF1) reduced locomotor hyperactivity in 4‐month‐old TgCRND8 mice and reversed the cognitive impairment compared to wild‐type animals. The reporter has shown that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model, which suggests the potential value of ROCK inhibitor for the promotion of cognition in humans 70. As discussed, inhibition of ROCK can promote spatial learning and working memory and regulate the metabolism of Aβ, which suggests that ROCK appears to be a good target for AD therapy.

Another downstream signaling molecule of Nogo‐A/Nogo‐A receptor is PKC. A growing body of recent studies illustrates that protein kinase C (PKC) signaling pathways are causally concerned about the pathology of AD 90. PKC plays crucial roles in synaptic plasticity and short memory. PKC can be activated by a variety of signaling systems, of which the calcium concentration is one of the key factors that mediate the activation of PKC, triggering short‐term synaptic plasticity. DAG activates PKC with the coordination of Ca²⁺ and then causes cascade reactions by protein kinases C 91. Once the calcium overload, it significantly increased the expression of calcium/calmodulin‐dependent protein kinase II‐α. As a result, PKC system is overactivated and inevitably damage neurons. PKC α and PKC β, two Ca²⁺ dependent PKC isoforms, are necessary for posttetanic potential (PTP), a form of plasticity responsible for underlining short‐term memory. Fioravante et al. 92 discovered that disruption of the PKCβ C2 domain binding to Ca²⁺ specifically prevents PTP, suggesting that the increase of Ca²⁺ evoked by tetanic stimulation leads PKC β to produce PTP. Thus, the shortage of PKC is hypothesized to be a reason for short‐term memory deficits of AD.

On the other hand, PKC regulates Aβ production and clearance 93. PKC is involved in the processing of the APP, subsequently leading to the abnormal production and accumulation of Aβ by the sequential actions of β‐secretase and γ‐secretase, which is deemed to be detrimental in the onset and development of AD 94. According to Yang et al. 95 research on SK‐N‐SH and PC12 cells, DAG stimulated the release of ɑ‐secretase form of soluble APP (sAPPɑ) in the nonamyloidogenic way. However, the increase of sAPPɑ secretion by deprenyl was blocked by the mitogen‐activated protein kinase (MAPK) inhibitor U0126 and PD98059 and PKC inhibitor GF109203X, indicating that deprenyl actives PKC and leads sAPPɑ to release. Other studies also show that blockade of PKCε activation decreased phorbol ester‐induced secretion of sAPPα 96. Since sAPPα was generated by nonamyloidogenic pathway, it can be hypothesized that the activation of PKC leads APP to metabolize mainly through nonamyloidogenic pathway and causally reduces its metabolism via β‐secretase pathway, which may indirectly decrease the secretion of Aβ. Therefore, PKC activators are regarded as a potent strategy in AD therapy.

Concluding Remarks

In summary, the Nogo‐A/Nogo‐A receptor plays an important role in AD pathology, and its effects and intrinsic mechanisms are thought to be related to the several key aspects. First, the Nogo‐A/Nogo‐A receptor and the downstream Rho‐ROCK pathway inhibits axon outgrowth and synapse remodeling, becoming an obstacle to neuronal regeneration and blocking the recovery of damaged neural networks in AD. Second, it influences the metabolism of APP. Nogo‐A and downstream signaling to ROCK contribute to the generation of Aβ, which may be a precipitating factor of neuronal degeneration and accelerate the onset of AD. In contrast, NgR could function by reducing Aβ production. The newly discovered protein S1PR2 is a novel receptor for Nogo‐A which also activates ROCK and mediates neuronal plasticity. Another newly discovered protein PirB is also a novel receptor for Nogo‐A that interacts with Aβ and mediates its neurotoxicity. As discussed, the effect of Nogo‐A and the Nogo‐A receptor signal system on the pathogenesis of AD is relatively complicated. Whether it promotes or delays the progress of AD depends on the expression and state of various proteins and the interaction of the different signaling pathways. Further study is necessary to clarify the exact effects and in‐depth mechanisms of the Nogo‐A/Nogo‐A receptor on AD pathogenesis. New strategies targeted at key proteins of Nogo‐A/Nogo‐A receptor signaling have emerged as potential interventions in the progression of AD and bring new hope for AD therapy.

Conflict of Interest

The authors declare no conflict of interest.