Nitric oxide has a dual role in Alzheimer's disease

[madman]

NO's role in Alzheimer's disease (AD) is complex and not fully understood. It has various functions in the body, including neurological control and cardiovascular regulation. Unlike conventional neurotransmitters, NO can passively cross cell membranes, affecting intracellular processes. It is associated with cellular function, signaling, neuroinflammation, and more, all relevant to AD. However, NO can have both neuroprotective and neurotoxic effects in AD. Future research should focus on human neuronal cell models to better understand NO's impact. Suppressing local immune response and promoting amyloid clearance may be crucial for AD treatment, rather than solely targeting neurotoxic signaling.

 

[madman]

Fig. 1. Pathway for NO synthesis. This pathway produces around 60% of the arginine in the kidney, compared to the endothelium’s 15% de novo arginine synthesis [28,32]. Arginine not only serves as a substrate for the production of NO, but it also aids the kidney’s production of urea [33]. The process of converting arginine to citrulline and urea is catalyzed by the enzyme arginase. As a component of the urea cycle, the cytosolic enzyme arginase is mostly expressed in the liver. A mitochondrial enzyme predominantly expressed in the kidneys is arginine II. Arginase I is present in human erythrocytes and is still active in plasma. In addition, urea and arginine are separated by arginase, resulting in ornithine [34]. At the same time, citrulline generated in the urea cycle can be converted back to arginine through the processes of argininosuccinate synthase and argininosuccinate lyase (ASL) [32]. Abbreviations mentioned in Fig. 1., ASL: Argininosuccinate Lyase; ASS: Argininosuccinate Synthase; BH4: Tetrahydrobiopterin; FNM: Flavin Mononucleotide; FAD: Flavin Adenine Dinucleotide; NO2- : KG: Kinase G Nitrite; NO3-: Nitrate; TCA: Tricarboxylic Acid; OTC: Ornithine Transcarbamylase; NADPH: Nicotinamide Adenine Dinucleotide Phosphate.

 

[madman]

Fig. 2. NO-cGMP signaling pathway. Guanylyl cyclases (GCs) use Mg2+ or Mn2+ as cofactors to produce cGMP from the cytosolic purine nucleotide GTP. In vertebrate cells and tissues, there are two types of guanylyl cyclases (GCs): one is a soluble, nitric oxide (NO)-sensitive cytosolic form, and the other is a plasma membrane-bound, natriuretic peptide (NP)- activated form (pGC). Three major categories of biological target molecules—cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and phosphodiesterases (PDEs)—are involved in the actions of cGMP once it has been generated. The positive regulation of PKG by cGMP results in long-term potentiation, increased CREB phosphorylation, increased CBF, increased BDNF, and decreased inflammation.

 

[madman]

Fig. 3. Oxidative and nitrosative stress caused by NO can trigger a number of mechanisms that lead to mitochondrial death, which are as follows: 1) production of endoplasmic reticulum stress (ERS); 2) up-regulation of p53; 3) activation of the p38 MAP kinase pathway; and 4) provocation of mitochondrial permeability transition (MPT). Apoptosis is the result of all these processes. It causes cell death and neurotoxicity, resulting in neurodegeneration and the development of AD

 

[madman]

Fig. 4. Potential nitric oxide sources downstream of the Aβ up-regulation event, one of the pathogenesis-related occurrences in AD.

 

[madman]

Fig. 5. Guanylyl cyclase, a soluble NO receptor, binds to NO and, through cGMP-mediated signaling, functions as either a pre- or post-synaptic messenger. Since synaptophysin is essential for the fusion of presynaptic vesicles, synaptophysin is phosphorylated by the cGMP-dependent protein kinase G (PKG) pathway, which is activated by NO as a neurotransmitter. This process can lead to potentiating and facilitating neurotransmission [157]. Synaptic glutamate release also triggers the activation of postsynaptic NMDA and AMPA receptors (NMDAR, AMPAR), which in turn causes Ca2+ to trigger nNOS. NO will diffuse to activate the sGC and produce cGMP, which can influence the release of presynaptic neurotransmitters and target various ion channels among other signaling tasks. An interaction between nNOS and CAPON causes a cascade of downstream MAP kinases to begin, thereby nuclear transcription

 

[madman]

Fig. 6. The NO mechanism to ameliorate memory in detail is that glutamate first activates NMDAR in hippocampal glutamatergic synapses. This receptor – NMDAR – needs stimuli for its activation, to wit: sodium (Na+) entry to depolarize the postsynaptic membrane and binding glutamate with glycine. Then, the magnesium (Mg2+) ion is separated from the channel, thus allowing the influx of cations, mainly Na+ and Ca2+, into the neuron. The postsynaptic membrane then can be depolarized by Na+; simultaneously, Ca+2 binds to calmodulin (CaM) and nNOS will be activated [237], thereby producing NO. Incidentally, Ca2+ triggers a signaling cascade that escalates a number of the AMPA receptors – by which Na+ can enter into the postsynaptic neuron. Notably, since NO is able to diffuse from the postsynaptic ending to the presynaptic in which the releasing vesicles are provoked by a GC-independent mechanism [238,239], it will form an activation loop named LTP [240,241], which is the physiological mechanism of memory, and also it induces CREB, resulting in promoting spine growth