1. Alzheimer's Disease Related Signalling

 

1.1. Neuroinflammation in Alzheimer’s Disease 

 

Neuroinflammation through intensifying Aβ and Tau pathologies is responsible for enhancing AD (Alzheimer’s Disease) (Zotova E et al., 2010) (Calabrò M et al 2020).

 

An extended neuroinflammation results in a rise in cytokines, which in turn prompts mitochondrial stress in neurons through Aβ signaling (Calabrò M et al 2020).

 

According to Calabrò M et al 2020 “IL-18 raises the levels of CdK5 (the inhibition of which results in enhancement of conditions of the individual with AD) and GSK3β, implicated in hyperphosphorylation of Tau” (Alvarez A et al., 1999) (Ojala J O et al., 2008) (Calabrò M et al 2020).

 

Neuroinflammation in Alzheimer’s Disease References

 

1.        Alvarez, A., Toro, R., Cáceres, A. & Maccioni, R. B. Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death. FEBS Lett. 459, 421–426 (1999).

2.        Calabrò, M., Rinaldi, C., Santoro, G. & Crisafulli, C. The biological pathways of Alzheimer disease: a review. AIMS Neurosci. 8, (2021).

3.        Ojala, J. O., Sutinen, E. M., Salminen, A. & Pirttilä, T. Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J. Neuroimmunol. 205, (2008).

4.        Zotova, E., Nicoll, J. A., Kalaria, R., Holmes, C. & Boche, D. Inflammation in Alzheimer’s disease: relevance to pathogenesis and therapy. Alzheimers. Res. Ther. 2, (2010).

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1.2. Oxidative Stress and Alzheimer’s Disease

 

In the early stages of AD the level of Oxidative Stress (OS) is raised in the individual brain and is responsible for AD severity and proliferation (Calabrò M et al., 2020). Oxidative stress can be boosted by Aβ and be a cause for the existence of ROS and RNS (radical oxygen and nitrogen species)., and this procedure is primarily associated with the activity of critical proteic mediators of OS such as NOX, TGFβ, NFκB and Nrf2 (Llanos-Gonzalez E et al., 2019) (Chen Y Y et al., 2019 as cited in Calabrò M et al., 2020) (Calabrò M et al., 2020).     

 

Tau phosphorylation and induction of microtubule destabilisation are induced by an increase in ROS and RNS concentration (Calabrò M et al., 2020). The destabilisation of microtubules results in a reduction in the activity of synapses, therefore microtubules function in the preservation of neuronal cells polarisation and intracellular trafficking is essential (Munoz P et al., 2020 as cited in Calabrò M et al., 2020) (Calabrò M et al., 2020).     

 

The balance between pro- apoptotic or anti-apoptotic responses, which can cause neurodegeneration, is maintained by OS level (Calabrò M et al., 2020). It is known that neuronal cellular activity can be reduced due to low level of ROS that can induce proliferative signals in these cells (Swerdlow R H and Khan S M., 2004 as cited in Calabrò M et al., 2020) (Calabrò M et al., 2020).    

 

ROS is also known to circuitously control the permeability to glucose in neuronal cells. ROS plays role in the reduction of AD neurons’ GLUT-3 expression (Calabrò M et al., 2020).  ROS is also responsible for the decrease in the expression of GLUT-1 in BBB (Blood Brain Barrier) (Calabrò M et al., 2020). This method of regulation of glucose within neuronal cells i.e. the cells that need high levels of energy for their proper functionality, can lead to the non desired outcomes as a result of glucose hypometabolism in the brain (Llanos-Gonzalez E et al., 2019) (Calabrò M et al., 2020).     

   

 Oxidative Stress and Alzheimer’s Disease References

 

1.        Calabrò, M., Rinaldi, C., Santoro, G. & Crisafulli, C. The biological pathways of Alzheimer disease: a review. AIMS Neurosci. 8, (2021).

2.        Chen, Y.-Y. et al. Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products. Free Radic. Biol. Med. 141, 141–149 (2019).

3.        Llanos-González, E. et al. Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease. Front. Neurosci. 13, (2020).

4.        Muñoz, P. et al. Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease. Mech. Ageing Dev. 189, 111250 (2020).

5.        Swerdlow, R. H. & Khan, S. M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med. Hypotheses 63, 8–20 (2004).