Influence of FOX genes on aging and aging-associated diseases - Elena Tschumak

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of homogenous serum-stable complex with targeting potential. Further, uptake of the complex in Neuro-2a, IMR32 and HepG2 cells analysed by confocal microscopy and fluorescence activated cell sorting, revealed selective requirement of GM1 for entry. Remarkably, systemic delivery of the fluorescently labelled complex (TARBP-BTP:siRNA) in ΑβPP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization in the cerebral hemisphere. Further, the delivery of siRNA mediated by TARBP-BTP led to significant knockdown of BACE1 in the brain, in both ΑβPP-PS1 mice and wild type C57BL/6. The study establishes the growing importance of fusion proteins in delivering therapeutic siRNA to brain tissues.” (Haroon et al., 2016, p. 1)

       PIK3K

      Gabbouj et al. (2019) describe in „Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway“ the PI3K-Akt signalling pathway, involved in microglia and astrocytes, as an important player in T2D pathogenesis and insulin mediation. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits and decreased Akt kinase phosphorylation is associated with AD, amyloid-β and tau pathologies. TWD intake leads to altered PI3K subunits-levels and of intranasal insulin to enhancement of PI3K-Akt signalling, improved memory in human trials.

      

       PIM1

      

      PRAS40 phosphorylation is regulated by Pim1 Velazquez et al. (2016) gave a strong evidence for interconnection between the mammalian target of rapamycin (mTOR), proline-rich AKT substrate, PRAS40-phosphorylation-levels and Aβ, tau pathologies and cognitive deficits.

       BACE1

      

      Das, B. and Yan, R. (2017) described in „Role of BACE1 in Alzheimer's synaptic function“ that Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) and BACE1 inhibition reduces Aβ-level in humans. BACE1 inhibitors could be an effective AD remedy.

      

       NFE2L2

      

      Otter et al. (2010) illustrated in „Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract“ how one haplotype allele of NFE2L2 gene, encoding the main regulators of the defence system against oxidative stress, age-related cataract and AD, Nrf2-protein, was associated with 2 years earlier age at AD onset and 4 years earlier age at surgery for posterior subcapsular cataract.

      

      

      According to Joshi and Johnson (2012)“The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases“ neurodegenerative relevant NF-E2 related factor-overexpression has a positive impact on Amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson. A cis-acting antioxidant response element regulates phase II detoxification enzymes via ARE-Nrf2 binding with the help of Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 has a positive effect on oxidative stress.

      Pajares et al. (2016) identified in „Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes“ the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance to amyloid β precursor protein, MAPT/TAU and AD. According to ENCODE for BACH1 and MAFK, that bind the NFE2L2-regulated enhancer ARE, 27 putative AREs in 16 autophagy-related genes were identified and twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes after NFE2L2 activation with sulforaphane.

      Saad El-Din et al. (2020) describe in „Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer's disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways“ the Nrf2 as a promising target for the prevention of Alzheimer's disease and vitamin D, its analogue, Maxacalcitol as crucial for improving AD cognitive functions via Keap1-Nrf2 signalling pathway.

      Rojo et al. (2017) also confirmed in „NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology“ NRF2 as a crucial regulator of multiple stress responses, which also protects against inflammation and proteotoxicity and ageing is associated with decline of its level. Young adult AT-NRF2-KO mice showed deficits in long term potentiation in the perforant pathway, learning and memory.

      Bahn et al. (2019) showed in „NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models“ BACE1 as the rate limiting Aβ generation enzyme. AD is accompanied by BACE1 and a BACE1 mRNA-stabilizing antisense RNA elevation. NRF2/NFE2L2 represses the BACE1 and BACE1-AS-expression via ARE promoters binding, independent of redox regulation. Also NRF2 improves cognitive deficits in animal models of AD, so the authors regard NRF2 as a possible key factor in prevention of early pathogenic process in AD.

       KEAP1

      Kerr et al. (2017) associate in „Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease“ Nrf2 with cell protection and an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD), provided in vivo evidence that specific inhibition of negative regulator of Nrf2 Keap1 can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide. Lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity in Nrf2 independent way.

       JAK / STAT signalling

      Nevado-Holgado et al. published 2019 „Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer's Disease Therapeutic Developmen“, where they combined GWAS results with the current knowledge of molecular pathways, real-world clinical data from six million patients, RNA expression across tissues from AD patients and rodent models and showed that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription pathway. They demonstrated Aβ induction by JAK-STAT anomalies and identified these genes as a potential target for therapeutic approach.

       SERPINH1

      Aβ and cytokines, involved in microglial activation, play a crucial role in neuroinflammation and AD. Yoo et al. published 2015 „ Amyloid-beta-activated human microglial cells through ER-resident proteins“ . They performed a proteomic analysis of Aβ-stimulated human microglial cells by stable isotope labelling with amino acids in cell culture combined with LC-MS/MS and clarified ER-resident proteins-level of PDIA6, PDIA3, PPIB and SERPINH1 was altered by 1.5 fold or greater. The researchers suggested that ER proteins play an essential role in human microglial activation by Aβ and could be important therapeutic targets for treatment of AD.

      Ezrin-Radixin-Moesin complex.

       α-secretases cleave the amyloid precursor protein to neuroprotective soluble APP ectodomain. Darmellah et al. (2012) show in „ Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein“ that the activation of ezrin, radixin, and moesin proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release and the ERM down-regulation via siRNA blocked it and P2X7R stimulation triggered its phosphorylation. Ezrin must translocate to the plasma membrane to interact with P2X7R and enzymes Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream.

      Vega et al. (2018) also demonstrated in „Ezrin Expression is Increased During Disease

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