Influence of FOX genes on aging and aging-associated diseases

FOXP2 and neurodegeneration

Several studies showed the significance of FoxP2 for the brain and skull development (Benítez-Burraco et al., 2015) but above all for the language. (Watkins et al., 2002; Vargha-Khadem et al., 1998; Middleton ad Strick, 2000; Watkins et al., 2002; Liegeois et al., 2003; Lai et al., 2003). The FOXP2 gene (formerly also known as SPCH1, TNRC10 or CAGH44) was mainly associated with important language functions. First, the FOXP2 became known through the work of Anthony Monaco and Svante Pääbo Group at the Institute for Evolutionary Anthropology of the Max Planck Society in Leipzig. They studied the linguistic deficient KE family and found an autosomal dominant missense point mutation in exon 14 of the 7th chromosome (in the 7q31 band guanine was replaced by adenine). This mutation replaced arginine (R) by histidine (H) at the position 553 R553H of the FOXP2 protein and caused an inhibition of the DNA-binding domain and the inoperability of the protein. Other FOXP2 mutations were also observed by dyspraxia patients. (MacDermot et al., 2005; O'Brien et al., 2003; Jiménez-Romero et al., 2016; Becker et al., 2015; Zeesman et al., 2006).

In 2016 described Tborres-Ruiz et al. a girl with inherited complete chromosomal rearrangement. This rearrangement was accompanied by a fracture proximal and distal to the FOXP2 gene and resulted in cognitive disabilities. The fracture in a new neuroblastoma cell line SK-N-MC led to the decline of FOXP2 and increase of MDFIC-P protein levels. The MDFIC-P gene is localized near FOXP2. The FOXP-2 significance for the childhood apraxia of speech (CAS) and other speech disorders were also described. (Morgan et al., 2017; Kurt et al, 2012)

The FOXP2 mutations are often accompanied by structural brain changes, so the new multimodal MRI study of an eight-year-old boy (A-II) with a de novo FOXP2 deletion by Liégeois et al. „Early neuroimaging markers of FOXP2 intragenic deletion“ (2016). The researchers described in their work significant bilateral structural abnormalities in the basal ganglia and in hippocampus. In the hippocampus, in the thalamus, in the globus pallidum and in the caudate nucleus a volume reduction was also observed in comparison to the control group of 26 healthy volunteers. The patients showed no detectable functional MRI activity by the repetition of nonsense phrases.

FOXP2 also plays a role in the visual system (Iwai et al., 2013; Horng et al., 2009), in psychiatric disorders, and in aging dependent frontotemporal degenerative dementia accompanied by speech disorders (Sanjuán et al., 2006; Park et al., 2014; Wang et al, 2016; Bacon and Rappold, 2012; Fisher and Scharff, 2009; Premi et al., 2012; Kumar, et al., 2011).

FOXP2 is important for brain development and communication in many animal taxa (e.g. songbirds, marine mammals, bats and possibly elephants) which learn to communicate through imitation and whose auditory processing needs to interact with motor control. (Scharff and Haesler, 2005)

Scharff and Petri (2011) emphasized in „Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language“ that FOXP2 shows different expression cycles in different neuronal subtypes and „the more efforts should be directed at identifying the genomic loci regulating temporal expression differences of FoxP2“.

Other members of the FOXP2 family show many parallels to FOXP2. (Viscard et al., 2017)

FOXP2 and Alzheimer

López-González et al., 2016 described in FOXP2 Expression in Frontotemporal Lobar Degeneration-Tau that reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick’s disease and in frontotemporal lobar degeneration-tau. This tau degeneration was linked to P301L mutation, that was associated with language impairment in comparison to age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. “Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. These findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies.” (López-González et al., 2016, p.1)

Padovani et al. investigated 2010 in „The speech and language FOXP2 gene modulates the phenotype of frontotemporal lobar degeneration“ the influence of genetic variations within FOXP2 in neurological disorders and how FOXP2 polymorphisms influences frontotemporal lobar degeneration. After neuropsychological examination as well as brain imaging of two-hundred ten FTLD patients and in 200 age-matched healthy controls the researchers evaluated four FOXP2 polymorphisms: rs2396753, rs1456031, rs17137124 and rs1852469 they observed no significant differences in SPECT images of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls, in the same time they reported a significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores and an addictive effect of two polymorphisms. Afterwards they computed the number of observations over time and obtained 391 comparable results that showed: FTLD patients carrying at-risk polymorphisms have greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers. Genetic variations within FOXP2 modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.

Di Meco et al. proposed 2019 in „Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology“ new insights in maternal history for sporadic Alzheimer’s disease (AD) and the possibility of susceptibility modulation to AD via gestational high fat diet. Triple transgenic dams (human PS1, human MAPT and KM670/671NL)

were fed with high fat diet: 42% calories from fat or regular chow 13% calories from fat throughout 3 weeks gestation. This study showed how gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-β and tau neuropathology (decrease in the levels of Aβ1–40 and Aβ1–42) in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. To proof that FOXP2 effects on tau,

CDK5 and BACE-1 the researchers exposed APPswe mutant N2A cells to FOXP2-GFP plasmid and measured tau, FOXP2, CDK5 and BACE-1 protein and mRNA levels 24 hours after, wich were decreased, but lower APP level was not observed. Behavioral impairments could be improved under and electrophysiology of 3TG hippocampal slices showed higher excitatory postsynaptic potentials as well as increasing strength of stimulus intensities. Longterm potentiation in the CA1 region of the hippocampus and paired pulse facilitation were measured and showed partial restoration of the

fEPSP in 3TG HF, also of neuronal plasticity and memory. So gestational high fat diet significantly decreases tau aggregation-prone isoforms level, soluble tau level as well as of its phosphorylated isoforms and protects this way offspring from later AD.

There is many evidences about indirect influence of FOXP2 on neurodegenerative diseases, so:

FOXP2 controls expression of for Alzheimer's disease relevant RELN (Adam et al.,2016)

Seripa et al. described 2012 in „The RELN locus in Alzheimer's disease. “ serine protease, encoded by the RELN gene, as part of in AD involved apoE pathways. The researchers investigated three polymorphisms in the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the exon 6 splice-junction and in the exon 50 coding region. The analysis of 223 sporadic AD patients 181 controls. There was no significant differences in rs2229874 but in 5'UTR and rs607755 genotypes, in females and not in males (even if APOE genotypes were adjustment). So RELN gene variants may effect AD pathogenesis of, especially in females.

In“ Reelin depletion is an early phenomenon of Alzheimer's pathology“ 2012 Herring et al. examined the expression profile of with Alzheimer's disease associated “RELN and its downstream signalling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging..”(Herring et al., 2012, p.1) Their results showed that “AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner” and the “depletion of RELN, but not its downstream signalling molecules, is detectable long before the onset of amyloid-β pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN's potential as a pre-clinical marker for AD.” (Herring et al., 2012, p.1)

FOXP-2 affects NCAM1, VLDLR and other target genes in the nervous system

FOXP2 controls expression of for Alzheimer's disease relevant glycoprotein NCAM1. (Atz et al., 2007) ( Konopka et al., 2009) The FOXP2 also influences DISC1, (Walker et al., 2012), (Miyoshi et al., 2004), a Reelin receptor VLDLR (Adam et al., 2016), NURR1, PHOX2B, TBX22, SEBOX and FOXL1, CDH4 and CDH11, DICER1, RISC TARBP2, DICER1, EIF2C1-4 , DCDC2, KIF13B, PTPRQ, MSN, FOXP2 , NAKR1, SEBOX, MARVELD1, PHOX2B, MYH8, MYH13, PIK3K, PTPRQ, PIM1, NFE2L2, ERP44, KEAP1, JAK / STAT signalling, the phosphatase PTEN, BACE2, SERPINH1, CDH4 and the Ezrin-Radixin-Moesin complex. These proteins are involved in nervous system myelination, neuroinflammation, amyloid precursor protein formation, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Lewy body dementia and Parkinson's disease (Devanna et al.,2014) Different of these targets play an important role in aging and can be affected via caloric restriction. The amount of satellite cells decreases with age (Brack et al., 2005; Collins et al., 2007; Gibson and Schultz, 1983) and like hematopoietic stem cells they change their Wnt and Notch pathways with the age as well as TGF-β and sFGF ligands and differentiate less to myogenic lineage and more to fibrogenic lineage Brack et al., 2007 Carlson et al., 2009 Carlson and Faulkner, 1989 Chakkalakal et al., 2012 ; Conboy et al., 2003, 2005; Sinha et al., 2014) and cytokine signalling via the JAK-STAT pathway (Price et al., 2014) and increase p38-MAPK signalling (Bernet et al., 2014; Cosgrove et al., 2014) Sousa-Victor et al., 2014 ). Wnt3, GH, TGF-β and IGF improve neurogenesis (Blackmore et al., 2009 Katsimpardi et al., 2014 ; Lichtenwalner et al., 2001; Okamoto et al., 2011; Pineda et al., 2013 ; Villeda et al., 2014 ).Growth differentiation factor 11 (GDF11)can improve NSC- and satellite cell function, but ist production decreases with aging. (Katsimpardi et al., 2014; Loffredo et al., 2013.; Sinha et al., 2014). At the same time high TGF-β levels disturb satellite cells and neuronal stem cells function (Carlson et al., 2009;) but growth differentiation factor 11 improves it. (Katsimpardi et al., 2014 ; Loffredo et al., 2013; Sinha et al., 2014).

Kanekiyo and Bu showed 2014 that Low-density lipoprotein receptor-related protein 1 regulates cellular Aβ uptake and degradation in neurons, astrocytes, and microglia in brain parenchyma, and in vascular smooth muscle cells and pericytes in cerebrovascular. It also mediates Aβ clearance at the BBB by facilitating Aβ transport from brain to blood and Apolipoprotein E is a major ligand for LRP1 and influences AD risk by affecting Aβ aggregation, cellular uptake and degradation, apoE and Aβ “can interact with each other, they also share common receptors including LRP1, LDLR, and HSPG on cell surface. ApoE likely competes with Aβ for their receptor binding but can also facilitate cellular Aβ uptake by forming apoE/Aβ complexes depending on their concentrations, apoE isoform involved, lipidation status, Aβ aggregation status and receptor distribution patterns. Dissecting how LRP1 participates in apoE-mediated Aβ clearance will be critical to develop apoE-targeted therapy for AD.” (Kanekiyo and Bu, 2014, p. 7)

FOXP2 controls expression of for Alzheimer's disease relevant PTEN (Oswald et al.,2017; Frere and Slutsky, 2016; Knafo et al., 2016; Zhang et al. 2006; Rickle et al., 2006) Mislocalization of Pten in murine brain was observed to correlate with down-regulation of Foxp2 and upregulation of Msn (Tilot et al., 2016)

Further FOXP2 controls expression of for Alzheimer's disease relevant glycoprotein NURR1 Nurr1 was specifically expressed in glutamatergic neurons of the hippocampus of healthy brains and that these Nurr1‐expressing, Aβ‐positive glutamatergic neurons degenerated in an age‐dependent manner in 5XFAD mice and plays important roles in AD pathogenesis. (Moon et al.Nurr1, 2019)

According to Oswald et al. (2017) „The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration“ the transcription factor encoded by the new FOXP2 target NURR1 (also NR4A2, NOT) seems to be of special importance for normal dopaminergic functioning. So stimulation of NURR1 improves behavioural deficits, associated with the degeneration of dopamine neurons in PD model mice – an effect which involves enhanced trans-repression of neurotoxic pro-inflammatory genes in microglia and increased transcriptional activation of midbrain dopaminergic (mDA)neurons (Kim et al., 2015). Nurr1 knockout mice even fail to develop dopamine neurons (Zetterström et al., 1997).

So dopamine-related diseases AD, PD SCZD, Lewy body dementia are accompanied by several NURR1 mutations. (e.g., Chen et al., 2001; Zheng et al., 2003; Chu et al., 2006).

FOXP2 controls expression of for Alzheimer's disease relevant glycoprotein NCAM1. (Gillian et al., 1994; Todaro et al.,2004 )

Moreover, NCAM1 is a putative target of both RUNX2 (Kuhlwilm et al., 2013) and FOXP2

(Konopka et al., 2009). In Boeckx and Benítez-Burraco “Globularity and language-readiness: generating new predictions by expanding the set of genes of interest”, the FOXP2 also influences Alzheimer relevant DISC1. Using dual luciferase assays Walker et al. (2012) demonstrated that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect and inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2). R553H and R328X FOXP2 point mutations found, known from developmental verbal dyspraxia affected families, decreases his inhibition. Further knockdown of DISC1 increases the expression of APP at the cell surface and decreases its internalization. (Shahani et al., 2015)

Further aging and neurodegeneration relevant FOXP2 targets

FOXP2 and Vitamin D effect on ZNS

FOXP2 target RUNX2 binds to the 1alpha, 25-dihydroxyvitamin D3 receptor. (Paredes et al., 2004). The 25-dihydroxyvitamin D3 receptor is encoded by VDR involved in immune response and tumor suppression. Together with the VDR express multiple immune relevant genes, eg. they regulate SPAG5. (Stephens and Morrison., 2014). The SPAG5 encodes a protein required for the correct function of mitotic spindles, which also regulates cell stress-induced apoptosis. (Thedieck et al., 2013) Together with FOXP2, RUNX2 regulates aging relevant vitamin D (Patrick and Ames, 2014), (Hawes et al., 2015) and other interaction partners, such as: CREB (Oury et al., 2010)

Aging relevant H3K27ac and H3K14ac are acetylated via p300/CBP and its co-activator CREB . cAMP responsive CREB expression is responsible to fasting. So CBP, CREB, CRTC2 and TAF-4 activate together gluconeogenesis genes (Altarejos and Montminy, 2011 )

The RUNX2 also affects GTF2I (Lazebnik et al., 2009), there is some evidence for feedback processes because both GTF2I and RUNX2 expression are regulated by the AUTS2. (Oksenberg et al., 2014) The AUTS2 cooperates with the PRC1, the GTF2I, the SATB2, the ZMAT3, the RELN and the TBR1.

Vitamin D-Esr1-Igf1 interaction effects molecular pathways relevant to Alzheimer’s disease and Molecular Neurodegeneration. (Landel et al.,2016)

Kaneko and colleges demonstrated that calcitriol regulates the expression of two human brain-related genes containing VDREs, tryptophan hydroxylase (Tph) and leptin. Landel et al, 2016 studied the effect of maternal vitamin D deficiency on fetal brain development and identified that these genes are also modulated in the brains of either Wt or Tg mice and found that the pups from deficient mothers display a modulated expression of Bdnf, Foxp2, Tgfb1 and Th, which are also affected in certain conditions of this study. Together with FOXP2, RUNX2 regulates aging relevant vitamin D (Patrick and Ames, 2014), (Hawes et al., 2015) and other interaction partners, such as: CREB (Oury et al., 2010).

Vitamins and aging

In general vitamins are also age-related factors. So, Vitamin D is important for ROS protection in the ZNS and for cell cycle regulation.( Pusceddu, 2015) Vitamin B2 is an antioxidant due to its involvement in the glutathione redox cycle (in glutathione reductase (Ashoori, 2014) and it is a cofactor in amino acid and lipid metabolism as well as in redox reactions. Riboflavin reduction increases lipid peroxidation. (Wang, 2011) Vitamin B6 reduces homocysteine concentrations and protects against cardiovascular diseases (Okura , 2014) Vitamin B12 is a cofactor for the methionine synthase (important for folate cycle and homocysteine re-methylation) and for the Methylmalonyl CoA mutase ( Hughes, 2013) Aging is associated with B12 reduction. Antioxidant Vitamin C (ascorbic acid) and dehydroascorbic acid are necessary for myelin, peptide amination, for synthesis of neurotransmitters and carnitine and it helps to recycle vitamin E and tetrahydrobiopterin, its deficiency is associated with amyloid-β plaques. ( Dixit, 2015) Like vitamin E (Gutierrez-Fernandez, 2015; Rinaldi, 2003) Vitamin A and retinoic acid are necessary for neurodevelopment (Touyarot , 2013) and its reduction is associated with aging, inflammation. It influences p21 and Alzheimer disease.

FOXP2 influence on RA receptor expression and its effect on the retinoic acid-mediated neuronal differentiation

Benítez-Burraco and Boeckx (2014) described in „FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways“ the importance of RA signalling and of FOXP2 for brain processes, the upregulation of RARβ by FOXP2 . The FOXP2 indirectly regulates the SIRT1 and other genes via RUNX-UTS2-TBR1-DYRK1A cascade and directly some SIRT1 target genes. The DYRK1A in turn phosphorylates the SIRT1. So there exists possible a connection between the FOXP2 and the RUNX2 via SIRT1. In addition, the SIRT1 directly controls thewith nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X RUNX2.The Dyrk1A also promotes de-acetylation of TP53, which is associated with carcinogenesis (Ni et al., 2005). TP53 induces PANDA lncRNA, which influence aging via binding the transcription factor NF-YA.

Sodhi and Singh, 2014 found in „Retinoids as potential targets for Alzheimer's disease“ that vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Both have an antioxidant potential. Retinoid signalling exists in including amygdala, hypothalamus, hippocampus, striatum and cortex and its defects seem to be relevant for defects in learning, memory and for Alzheimer's disease. Retinoids also decrease pro-inflammatory cytokines- and chemokines-level by astrocytes and the microglia. RA exposure leads to an up-regulation of choline acetyltransferase (ChAT) level and activity, ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation in APP/PS1 transgenic mice and its isomers enhance, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1 and abcg-1 proteins in astrocytes.

Also according to Das et al..2019 „Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer's disease“ retinoids have an important impact on neural patterning, differentiation, axon outgrowth and brain function, impaired RA- signalling leads to oxidative stress, mitochondrial malfunction, neuroinflammation, neurodegeneration and Alzheimer's disease (associated with aggregated amyloid-beta and hyperphosphorylated tau protein). They also described loss of spatial learning and memory as a result of low RA-level, because retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer's disease. Retinoic acid receptors stimulation decreases amyloids accumulation,neurodegeneration level, and thereby prevents pathogenesis of Alzheimer's disease in mice.

Shudo et al. published 2009 „Towards retinoid therapy for Alzheimer's disease. “This paper deals mainly with AD in relation to retinoic acid receptors (RARs: RARα, β and γ) and their ligands (retinoids), such as the endogenous RAR ligand all-trans-retinoic acid (RA), considering current knowledge about PD, ALS and other neurodegenerative diseases. “It is important to note that factors leading to the onset of these diseases are still poorly understood, and so there is a great deal of scope for novel therapeutic approaches. Recent findings indicate that the window of opportunity for enhancing or normalizing the growth of neuronal cells and promoting recovery from neurodegenerative diseases may be larger than previously thought.” (Shudo et al., 2009, p.1)

Another direct FOXP2 target is the general transcription factor GTF3C3, which plays an important role among others in apoptosis (Zhan Y, 2002).

According to Devanna et al. (2014) "FOXP2 drives neuronal differentiation by interacting with retinoic acid signalling pathways", FOXP2 interaction with retinoic acid makes cells more sensitive to RA effects and strengthens this way neuronal differentiation. This leads to increased neurite growth and branching as well as to decreased neuronal migration. These effects are particularly important in the striatum because speech-disabled people with a mutant FOXP2 gene have a pathology in this brain area. This gives further hint to the FOXP2 role in neuronal differentiation. The authors also mentioned that FOXP2 reduces DDL3 and RARβ (retinoic acid receptor) expression in the striatum.

In “Retinoic Acid Signaling: A New Piece in the Spoken Language Puzzle” (Rhijn et al. 2015) looked the researchers for evidence that the FOXP2 and RA pathways overlap. They analysed molecular, cellular and behavioural levels and found that FOXP2 changes RA receptor expression. These receptors directly control cellular response to RA. The retinoic acid receptor β (RAR β) was of particular interest because mice with the corresponding mutation showed severe movement deficits and its motor learning was severely impaired. (Krezel et al.) Increased RA level in pregnant rats led to behavioural problems and to impaired learning, memory and motor function. (Holson et al., 1997) Rats with a vitamin A deficiency also showed poor motor performance when they learned new movements. (Carta et al., 2006) In addition vitamin deficit had a negative impact on striatal development. Striatal progenitor cells could not differentiate without RA signals (Krezel et al., 1998), (Chatzi et al.,2011). Acute RA-level reduction in mice led to impaired induction in synaptic grading and impairment of hippocampal LTP and LTD, which was, however, reversible. Normal synaptic plasticity was quickly restored in this phenotype with the help of vitamin A supplementation. (Misner et al., 2001)

According to Boccardi et al. „Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects“, 2019 β-carotene significantly and positively correlated with telomerase activity, independent of gender, Β-carotene plasma level was associated with AD diagnosis and

β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates. This way FOXP2 genes can have a further effect on aging and tumorigenesis.

According to Devanna et al. (2014) „FOXP2 drives neuronal differentiation by interacting with retinoic acid signalling pathways“ FOXP2 reduces the expression of DDL3 and RARβ (retinoic acid receptor). The CARET study showed that high-dose beta-carotene (a precursor of retinoic acid (vitamin A) for an extended period was suspect to cause by 18 percent smokers lung cancer and it is known that FoxP2 is high expressed in lungs (Li, et al., 2004; Zhou et al., 2008;Groszer et al., 2008). FoxP2-coexpression with the transcription factor homeodomain Nkx2.1 in the lung was described by Li et (2012) FoxP2 interaction with the CtBP1 co-repressor may be involved in tumor suppression of breast cancer. CtBp interacts with the oncofactor BRCA1 / 2 (Chinnadurai G., 2009) (Deng et al. 2012) It would be of great interest to investigate whether the pathogenic vitamin A effect in this case is due to the interactions with FOXP2 which play a role in many oncological processes.

CDH4

According to Liu et al., 2012 total cerebral brain volume depends on CDH4-level, involved also in AD.These findings suggest that Dicer1 may be a target in AD therapy.

DICER1

Yan et al. (2019) explained that Dicer1 is reduced in APPswe/PSEN1dE9 mice and is regulated by Nrf2 and Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2. The researchers studied unexploited roles of Dicer1 in AD and a novel way of Dicer1 regulation. Their results make hope that Dicer1 may be a target in AD therapy.

TARBP2

According to Haroon et al., 2016 „A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain“TARBP2 Binding Protein fused to a brain targeting peptide that binds to monosialoganglioside GM1. “Conformation-specific binding of TARBP2 domain to siRNA led to the formation 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.