Netrin–1 are chemotropic proteins that belong to the family of laminin-related secreted proteins.
1. Netrin Receptors
Netrin–1 are chemotropic proteins that belong to the family of laminin-related secreted proteins
[1]. Involved in axon guidance, these proteins are located in the somatic mesoderm of the central nervous system and in the ventral region of the spinal cord, specifically in the neuroepithelial cells and the floor plate, and non-neuronal areas such as the pancreas and cardiac muscle
[2]. These proteins are responsible for guiding cell and axon migration during neural growth and development
[3]. They possess antiapoptotic
[4] and anti-inflammatory properties
[5], and are instrumental during neurogenesis, angiogenesis, and morphogenesis
[6]. netrin–1 response is mediated by the family of UNC5 and DCC (deleted in colorectal carcinoma) receptors. Netrin–1 is bi-functional in nature, attracting some axons while repelling others
[7]. UNC5 is responsible for directing the signal away from the netrin source (chemo repulsion), while, DCC is responsible for chemo attraction, but only when located at a distance from the source of netrin–1. DCCis also involved in repulsive processes
[8].
2. Specifics
Netrin–1 receptor has proapoptotic activity. Thus, in the absence of netrin-1 receptor, DCC and UNC5, netrin dependent receptors, incite cellular apoptosis
[9]. Where, UNC5 receptors mediated apoptosis by activating death-associated protein kinase (DAPK), particularly, the abnormal UNC5C contributes to AD by activating death-associated protein kinase 1 (DAPK1)
[10]. Furthermore, the deficiency of netrin–1 has also been shown to cause a missense mutation (T835M) in the UNC5C receptor, resulting in late-onset Alzheimer’s disease (LOAD). The over expression of T835M-UNC5C can induce the nerve cell death and increase the risk of LOAD, however, the neuronal cell death can be inhibited by netrin-1 binding to UNC5C on the cell surface
[11]. Nonetheless, the molecular mechanism of the receptor is unclear. Recently, Chen et. al. have shown that neurodegeneration in AD is facilitated by the selective cleavage of UNC5C, by the action of δ-secretase, contributing to AD pathogenesis. δ-secretase is activated in the absence of netrin which then distinctively cuts UNC5C at the N467 and N547 residues, supplementing caspase-3-activation and neuronal cell death. In APP/PS1 mice, the expression of δ-secretase truncated UNC5C fragments enhanced AD pathologies, thereby reducing learning and memory capabilities. Simultaneously, when UNC5C was removed from these mice, they regained cognitive disorder and weakened AD pathogenesis
[12].
In addition, gene polymorphism in netrin–1 and its receptor have also been linked with AD pathogenesis. In the adult mammalian brain, mutations in the receptor proteins are involved in neurodevelopment and neurodegeneration disorders. Synaptic plasticity during learning and memory development is controlled by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor (AMPA glutamate receptor) transport at excitatory synapses. Thus, the molecular mechanisms in relation with the synaptic function of netrin-1 presents a new therapeutic target for neuropathology related to memory dysfunction including Alzheimer’s disease
[13].
Several reports have additionally illustrated role of netrin–1′s role and its effect on AD pathology via Aβ production. Shabani et al. demonstrated that injection of netrin-1 in rats improved the amyloid-β-mediated suppression of learning-memory and synaptic plasticity. This study was included field potential recording and behavioral experimentation. They found that repeated administration of netrin–1 or its vehicle ameliorated neurotoxicity induced by Aβ and participated only in the recovery of the late phase of long-term potentiation (LTP) and did not contribute to the induction of early HFS-LTP (High frequency stimulation – long term potentiation)
[14]. Likewise, Zamani et al. also investigated the effect of netrin-1 microinjection on memory impairment in a rat model of AD. They observed that in novel object recognition task (NOR), administration of netrin-1 enhanced cognitive dysfunction. At the same time, using the Morris water maze (MWM) setting, they also observed reduced spatial memory progression and reduced amyloid aggregation
[15]. Nonetheless, netrin-1′s molecular mechanism associated with in spatial memory improvement and cognition is unclear. However, these studies provide a plausible therapeutic target for the treatment of AD in relation to the role of netrin–1 in AD pathology. These studies strongly support the implication of netrin signaling in AD pathogenesis. Netrin-1 consequently, serves as a complementary target for blocking neuronal cell death, ameliorating synaptic plasticity, and learning-memory functions induced by amyloid beta peptides.
The pathophysiology of AD is complex and one needs to consider several factors in comprehending the main component/s leading to memory loss, learning difficulties, poor judgement, and cognitive dysfunction. This review highlights the importance of receptors and neurotransmitters in synaptic signaling and cognitive function. This approach bridges the gap in our understanding of this enigmatic neurodegenerative disease, but also identifies prospective therapeutic targets to treat AD pathology. In this context, the pharamacological approaches and drug development methodologies for treating AD should be able to reverse the cognitive and synaptic impairments and reduce amyloid burden. While Aducanumab was recently approved by the FDA to remove Aβ plaques from the brains of AD patients, there is no definite proof that those AD patients will be able to regain their learning and memory functions. Consequently, defining the roles of receptors in synaptic transmission based on their significance in modulating nerve signals for a normal functioning brain, will enable researchers broaden understanding of AD pathology. Table 1 provides further insight of additional targets that have an essential role in cognitive functions.
Table 1. Promising therapeutic targets for ameliorating AD.
Astrocytes are the non-neuronal cells that are involved in regulating neuronal health and blood brain barrier (BBB). They contribute towards neuronal development and homeostatic maintenance of neurotransmitters, glutamate and GABA
[29]. They also serve as a target for ganglioside GM1 for mediating its cerebral energy metabolism and neuroprotective effect
[16]. Thus, a dysfunctional astrocyte is characterized with a wide variety of neurodegenerative disease, such as AD, Parkinson’s disease, Huntington’s disease and Rhett syndrome
[29]. In AD, reactive astrocytes are closely linked with Aβ peptides. They are considered as a direct modulator of synaptic transmission and neuronal functioning, resulting into impaired cognition in AD. Thus, targeting reactive astrocytes for reducing reactive astrogliosis is considered as a potential therapeutic approach for ameliorating cognition in AD
[17]. Similarly, the astrocytic circadian clock is considered as a regulator for inducing the inflammation of Chi3l1 protein. Chi3l1/YKL-40 is a glycoprotein that is encoded by Chi3l1 gene. It is mainly expressed in astrocytes in the brain and is elevated during the inflammation of neurons in AD. Chi3l1/YKL-40 is also a potential therapeutic target for slowing the progression of AD and modulating the activation of glial phagocytosis and amyloid deposition in mice
[18].
Low density lipoprotein receptor (LDLR) regulates the amount of cholesterol in the blood. It consists of cell surface proteins that are involved in endocytosis of plasma lipoprotein containing ApoE. The overexpression of LDLR have been reported in ameliorating cognitive decline by reducing tauopathy
[19]. The expression of LDLR is modulated by Idol, an E3 ubiquitin ligase. The down regulation of Idol increases the concentration of LDLR in brain with the subsequent reduction in the amount of ApoE, amyloid plaques and finally ameliorating neuroinflammation via LXR-Idol pathway
[20]. Thus, LDLR in relation to ApoE is crucial in removing plaques and tangles and serves as a potential therapeutic target for treating AD pathogenesis.
Notch receptors (notch signaling) are highly expressed in the hippocampal area. These are instrumental in vascular development and also in determining the fates of neuronal and non-neuronal cell in development. The expression level of notch receptors changes in dementia patients and are closely associated with the risk of development of AD pathogenesis
[21][22][23]. Likewise, the collagen receptor glycoprotein VI (GPVI) was reported to be involved in the promotion of platelet mediated amyloid aggregation in cerebral vessel through integrin αIIbβ3. Thus, inhibiting such processes may improve the vascular symptoms and cerebral amyloid angiopathy that contributes to dementia in AD patients
[24][25]. Similarly, the elimination of orphan G-protein coupled receptor (GPR3) that mediates the amyloidogenic proteolysis significantly diminished the amyloid plaques and ameliorated memory in the transgenic AD mouse models
[26]. And, in recent studies, the epigenetic modification, histone methylation, have been implicated in aging and neurodegenerative disorders. The epigenetic mechanism is crucial for learning and memory processes and serves as a possible therapeutic approach for AD pathogenesis
[27][28].