Bone is a dynamic tissue that is continuously remodelled, a process that requires equal amounts of osteoclastic bone resorption and osteoblastic bone formation. Inflammation may disturb the equilibrium and result in local and/or systemic bone loss. Negative bone mass balance occurs in several chronic inflammatory diseases, e.g. periodontitis and rheumatoid arthritis (RA). The aetiology of periodontitis is infectious, while RA is an autoimmune disease. Despite aetiological differences, an association between the two diseases has been established but it is not known if they are causally related. Periodontitis may develop when the inflammatory process, initially restricted to the gingiva (gingivitis), further invades the periodontium and causes bone resorption. The cellular and molecular mechanisms underlying the transition from gingivitis to periodontitis are not fully elucidated. Osteoclast formation is dependent on receptor activator of nuclear factor kappa B ligand (RANKL), but how osteoclast precursors are recruited to the jawbone is poorly understood. A family of cytokines named chemokines has been reported to possess such properties and increasing evidence points towards their involvement in the pathogenesis of chronic inflammatory diseases. The overall aim of this thesis was to gain extended knowledge about the role of chemokines and a newly discovered family of leukocytes named innate lymphoid cells (ILCs) in periodontitis and concomitant inflammatory disturbed bone remodelling. Furthermore, the aim was also to study the association between periodontitis and RA. We identified increased serum levels of monocyte chemoattractant protein (MCP)-1 and CCL11 in individuals with periodontitis. Moreover, a robust correlation between the two chemokines and periodontitis was detected in a weighted analysis of inflammatory markers, subject characteristics and periodontitis parameters. We detected higher MCP-1 levels in periodontitis tissue compared to non-inflamed. Furthermore we demonstrated that human gingival fibroblasts express MCP-1 and CCL11 in response to pro-inflammatory cytokines through NF-κB signalling. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that the expression increased under inflammatory conditions. Osteoclasts did not express CCL11, but its high affinity receptor CCR3 was upregulated during osteoclast differentiation and found to co-localise with CCL11 on the surface of osteoclasts. Exogenous CCL11 was internalised in osteoclasts, stimulated the migration of osteoclast precursors and increased bone resorption in vitro. To analyse if periodontitis precedes RA we analysed marginal jawbone loss in dental radiographs taken in pre-symptomatic RA cases and matched controls. The prevalence of jawbone loss was higher among cases, and the amount of jawbone loss correlated with plasma levels of RANKL. In the search of the newly discovered ILCs, we performed flow cytometry analyses on gingivitis and periodontitis tissue samples. We detected twice as many ILCs in periodontitis as in gingivitis. In addition we found RANKL expression on ILC1s (an ILC subset). In conclusion, we demonstrated that CCL11 is systemically and locally increased in periodontitis and that the CCL11/CCR3 axis may be activated in inflammatory disturbed bone remodelling. We also found that marginal jawbone loss correlated with plasma levels of RANKL and preceded clinical onset of symptoms of RA. Furthermore, we demonstrated that ILCs are present in periodontitis and represent a previously unknown source of RANKL. / Skelettet har flera viktiga funktioner i kroppen såsom att möjliggöra en upprätt hållning, utgöra fäste för muskler och mediera rörelse, skydda benmärgen och de inre organen samt reglera mängden av lösligt mineral i blodet. Med tiden uppstår mikroskador i skelettet vilket innebär att benvävnaden måste byggas om för att vara fortsatt funktionell. Ombyggnaden kallas remodellering och är en kontinuerlig process som huvudsakligen utförs av benbildande celler kallade osteoblaster och bennedbrytande celler kallade osteoklaster. Remodelleringen är strikt reglerad av olika signalmolekyler och under friska förhållanden råder jämvikt mellan mängden ben som bryts ner och mängden ben som bildas, vilket innebär att benmassan hålls konstant. Vid sjukdomar som medför långvariga inflammationsprocesser i benvävnad eller i närheten av benvävnad, exempelvis parodontit (tandlossningssjukdom) och ledssjukdomen reumatoid artrit (RA), kan den rådande jämvikten rubbas, vilket oftast resulterar i minskad benmängd. Vid parodontit är den bakomliggande orsaken till inflammationen bakterier som finns i placket på tänderna, men vid RA tros anledningen vara att immunförsvaret attackerar kroppsegna celler. Trots olikheterna delar de två sjukdomarna flera gemensamma drag med avseende på riskfaktorer, vilka signalmolekyler som återfinns i blodet samt hur inflammationsprocessen fortskrider. Parodontit föregås av gingivit (tandköttsinflammation). Hos vissa individer övergår gingivit till parodontit, en process som inkluderar nedbrytning av tandens stödjevävnader inklusive käkben. Det är inte helt klarlagt vilka celler och molekyler som finns närvarande vid gingivit respektive parodontit eller vilka mekanismer som ligger bakom skiftet mellan de två tillstånden. Det är sedan tidigare känt att molekylen RANKL är viktig för osteoklastbildning, men det är delvis okänt hur osteoklastförstadieceller rekryteras från blodcirkulationen till käkbenet. En grupp av molekyler kallade kemokiner, som även finns i förhöjda nivåer i blod vid parodontit och RA, har visat sig ha sådana egenskaper. För att finna läkemedel som kan förhindra bennedbrytning till följd av den inflammatoriskt störda benremodellering som sker vid både parodontit och RA är det viktigt att studera sambandet mellan sjukdomarna och få en tydlig bild av vilka celler som är närvarande vid inflammationsprocessen. Det är även av betydelse att kartlägga vilka celler och molekyler som främjar rekrytering av osteoklastförstadieceller och bidrar till bennedbrytning. Syftet med den här avhandlingen var att undersöka betydelsen av kemokiner vid inflammatoriskt störd benremodellering och vid parodontit samt att undersöka sambandet mellan parodontit och RA. För att skapa en tydligare bild av vilka cellertyper som är närvarande vid inflammationsprocessen vid parodontit undersöktes även förekomsten av en nyligen upptäckt celltyp vid namn ILCimmunceller (ILCs) samt om dessa celler uttrycker RANKL. Först analyserades förekomsten av olika inflammatoriska signalmolekyler i blod från individer med parodontit samt från friska kontroller. Individer med parodontit hade förhöjda nivåer av kemokinerna MCP-1 och CCL11. Genom att använda en statistisk analysmetod som utöver inflammatoriska signalmolekyler även inkluderade kliniska variabler kunde ett samband mellan de två kemokinerna och parodontit påvisas. Vidare undersöktes möjliga ursprung till de i blodet förhöjda kemokinnivåerna genom att analysera tandkött från tänder med parodontit samt friskt tandkött. Vid parodontit uppmättes högre nivåer av MCP-1. Gingivala fibroblaster (en celltyp som producerar bindväv och ansvarar för tandköttets uppbyggnad) från människa bildade MCP-1 och CCL11 när de stimulerats med inflammationsfrämjande substanser, vilket krävde aktivering en intracellulär signaleringsväg kallad NF-κB. För att utreda betydelsen av CCL11 vid inflammatoriskt störd benremodellering analyserades bencellers bildning av CCL11 in vivo i skalltak från möss samt in vitro i cellodlingar. Osteoblaster bildade CCL11 in vivo och in vitro och bildningen ökade under inflammatoriska förhållanden. Osteoklaster bildade inte CCL11, men däremot fanns ett uttryck av receptorn CCR3, vilket är en mottagarmolekyl till CCL11. I vävnadssnitt från skalltak visades att CCL11 och CCR3 ser ut att binda till varandra på osteoklasternas yta. Dessutom hade CCL11 en positiv effekt på rekrytering av osteoklastförstadieceller och CCL11 som tillsattes till cellodlingar togs upp av osteoklaster och stimulerade benresorption. För att studera sambandet mellan parodontit och RA analyserades käkbensförlust vid tänder med hjälp av röntgenbilder tagna på individer som senare utvecklade RA (pre-symptomatiska) samt matchade kontroller. De presymptomatiska individerna hade en högre grad av käkbenförlust och det fanns också ett samband mellan käkbensförlust och nivåer av RANKL i blodet. Förekomsten av ILCs i tandkött från tänder med gingivit respektive parodontit analyserades med flödescytometri. Dubbelt så många ILCs återfanns vid parodontit än vid gingivit, varav majoriteten bestod av ILC1 (en undergrupp till ILCs). Vidare analyser visade att ILC1 cellerna bildar RANKL. Sammanfattningsvis, vid parodontit finns förhöjda nivåer av CCL11 i vävnaden och i blodet, och interaktionen mellan CCL11 CCR3 kan vara av betydelse vid inflammatoriskt störd benremodellering. Käkbensförlust föregår RA och korrelerar med nivåer av den osteoklaststimulerande molekylen RANKL i blodet, vilket stödjer teorin om att det finns ett samband mellan de två sjukdomarna. De nyligen upptäckta ILCs återfinns vid både gingivit och parodontit och utgör dessutom en tidigare okänd källa till RANKL.

The recent advances in molecular and computational biology have made possible the study of complicated transcriptional regulatory networks that control a wide range of biological processes and phenotypic traits. In this thesis, several approaches were combined including next generation sequencing, gene expression profiling, chromatin and RNA immunoprecipitation, bioinformatics and genome editing methods in order to characterize the biological significance of the ZBED6 and ZC3H11A genes. A mutation in the binding site of ZBED6, located in an intron of IGF2, disrupts the binding and leads to 3-fold upregulation of IGF2 mRNA in pig muscle tissues. The first part of the thesis presents a detailed functional characterization of ZBED6. Transient silencing of ZBED6 expression in mouse myoblasts led to increased Igf2 expression (~2-fold). ChIP-seq analysis of ZBED6 and histone modifications showed that ZBED6 preferentially binds active promoters and modulates their transcriptional activities (paper I). In the follow-up studies using CRISPR/Cas9 we showed that either the deletion of ZBED6 or its binding site in Igf2 (Igf2ΔGGCT) led to more than 30-fold up-regulation of Igf2 expression in myoblasts. Differentiation of these genetically engineered cells resulted in hypertrophic myotubes. Transcriptome analysis revealed ~30% overlap between the differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with significant enrichment of muscle-specific genes. ZBED6-overexpression in myoblasts led to cell cycle arrest, reduced cell viability, reduced mitochondrial activities and impaired the differentiation of myoblasts (paper II). Further studies on cancer cells showed that ZBED6 influences the growth of colorectal cancer cells with dramatic changes in the transcription of hundreds of cancer-related genes (paper III). The phenotypic characterization of Zbed6-/- and Igf2pA/mG mouse models showed that the ZBED6-Igf2 axis has a major effect on regulating muscle growth and the growth of internal organs. Transcriptome analysis demonstrated a massive up-regulation of Igf2 expression (~30-fold) in adult tissues, but not in fetal tissues, of transgenic mice (paper IV). In the second part of the thesis we investigated the cellular function of Zc3h11a, the gene harboring ZBED6 in one of its first introns. The function of the ZC3H11A protein is so far poorly characterized. We show that ZC3H11A is a novel stress-induced protein that is required for efficient mRNA export from the nucleus. The inactivation of ZC3H11A inhibited the growth of multiple viruses including HIV, influenza, HSV and adenoviruses (paper V).

Direct studies of speciation are possible in the superspecies complex of Drosophila paulistorum, which consists of six different semispecies undergoing incipient speciation. Strict maternal inheritance of mitochondria is the most common pattern of mitochondrial inheritance in animals. Here I show that paternal transmission of mitochondrial DNA occurs in the heteroplasmic Orinocan semispecies and is not limited to hybrid offspring. Inheritance of one mitotype is mainly maternal while the other is mainly paternal; a highly unusual pattern of mitochondrial inheritance. I used absolute quantification real-time PCR on DNA extracted from eggs and imagoes from the Amazonian and Orinocan semispecies, as well as hybrids between these two semispecies. In crosses performed between F1 hybrids with a combination of mitotypes not found in any of the parents, no F2 hybrids were acquired. One possible explanation for this is that differences in mitotypes and inheritance patterns of mitochondrial DNA may cause incompatibilities between the genomes of D. paulistorum. This may be one cause of hybrid inviability and genetic isolation between semispecies, a necessary part of the speciation process. This further complicates the story of the ongoing speciation process in the D. paulistorum superspecies complex, which offers much to learn about speciation, mitochondrial inheritance and interactions between multiple genomes in the same organism.

<p>During gestation, the maternal liver undergoes various adaptive changes to cope with the increasing physiological and metabolic demands from both maternal and fetal compartments. Among these changes are robust growth and changes in transcriptome profile. However, how these events happen, and other aspects of this physiological phenomenon remains unexplored. Therefore, we aimed at further understanding how maternal liver responds to pregnancy. We used BrdU labeling combined with a virus-based tracing approach to quantify the percentage of maternal hepatocytes undergoing DNA synthesis and division over the course of gestation in mice. </p> <p>We found that ~50% maternal hepatocytes entered S-phase but, unexpectedly, did not undergo cytokinesis. This strongly suggests that maternal hepatocytes in fact undergo endoreplication instead of hyperplasia, as believed previously. Pericentral Axin2⁺ hepatocytes were reported to behave as liver stem cells responsible for liver homeostasis and turnover. We generated an <i>in vivo</i> fate-tracing mouse model to monitor the behavior of these cells in the maternal liver. Our results showed that they did not proliferate during pregnancy, homeostasis, and following partial hepatectomy. Curiously, we uncovered that, hepatocytes exhibit developmental phenotypes at mRNA level pre-pregnancy and at both mRNA and protein level during pregnancy. In the non-pregnant state, hepatocytes reserved mRNA expression of liver progenitor marker genes <i>Cd133</i> and <i>Afp</i>, which are localized in the nuclei, without protein translation. During gestation, maternal hepatocytes displayed cytoplasmic translocation of <i>Cd133</i> and <i>Afp</i> transcripts, concomitant with corresponding protein expression. </p> <p>Overall, all maternal hepatocytes became CD133⁺, and a subset of them express AFP. Additionally, in non-pregnant livers, mRNA of <i>Epcam</i>, another liver progenitor marker, was expressed within majority of hepatocytes, whereas its protein was solely translated in the pericentral region. In contrast, by end-gestation, EPCAM protein expression switched to the periportal region. These observations indicate that maternal hepatocytes exhibit heterogeneous developmental phenotypes, partially resembling fetal hepatocytes. It is intriguing why mature hepatocytes dedifferentiate into a progenitor state in response to pregnancy. AFP is considered to be produced primarily from fetal liver and thus is used to evaluate fetal development health. </p> A potential clinical relevance of our data is that we identified maternal liver as a new source of AFP. The hippo signaling pathway has been shown to potently control liver growth and hepatocyte heterogenicity. Surprisingly, we found that pregnancy neither altered the expression nor activities of the components of this pathway and its effector YAP1/TAZ. This finding indicates that pregnancy-induced maternal liver growth is not driven by hippo-YAP1 pathway. However, we demonstrate that the presence of YAP1 is essential for CD133 protein expression in maternal hepatocytes. Collectively, we revealed that, as pregnancy advances, maternal hepatocytes likely undergo endoreplication and display developmental phenotypes. Mechanistically, YAP1 dictates the expression of CD133, contributing to the pregnancy-dependent phenotypic changes of maternal hepatocytes.

<p> The plant cytoskeleton is commonly considered a vital component of cell growth and development; however, it also plays a critical role in plant immunity. During plant immunity, the cytoskeleton orchestrates rapid and precise immune-associated processes. For instance, the cytoskeleton mobilizes and orients the movement of organelles, proteins, and chemical signaling. To counter plant immunity, bacterial pathogens deliver virulence proteins, known as T3Es (type III effectors), into plant cells through a needle-like apparatus called the type III secretion system (T3SS). A novel T3E, called RipU, interacts with the cytoskeleton. Data has shown that RipU co-localizes with cytoskeletal markers in tobacco leaves. Ectopic expression of RipU can suppress PTI responses like ROS bursts or seedling growth inhibition. Tomato plants inoculated with <em>Rs</em> K60 lacking RipU showed less wilting and root colonization, suggesting that RipU plays a role in pathogenesis and virulence. Furthermore, inducible expression of RipU in Arabidopsis dramatically alters plant development. These plants have wavy roots, branching root hairs, and underdeveloped true leaves. Our results suggest that by targeting the cytoskeleton, RipU contributes to <em>Rs</em> K60s pathogenicity and virulence. </p>

<p>Nitrogen and phosphorus are the two macronutrients which play important roles in the plant, both structurally and functionally, e.g., starting from being constituents of cellular integrity to being signal molecules in signal transduction. Since they are required by plants in higher concentrations, it becomes indispensable to replenish their pools in soils by the application of chemical fertilizers. However, this practice is not only costly, the sources of Phosphorus and Nitrogen are not renewable and the excessive application in the form of fertilizers is not environmentally sustainable. Therefore, it warrants a better understanding of the plant responses during the nutrient deficiency because such knowledge will help implement strategies for breeding crops with more efficient use of minerals.</p><p>Most prior efforts in studying the molecular and physiological responses to low minerals were focused on roots. However, recently it has been found that shoot-to-root long distance signaling plays an important role in the adaptation of roots to low nitrogen or phosphorus. Here, we measured different physiological and morphological parameters and used RNA-Seq to elucidate the physiological and molecular responses in the vascular tissues of <i>Plantago major</i>, a new model species established in our laboratory, to low nitrogen, low phosphate or combined nitrogen and phosphate starvation<i>. </i>In this study, <i>P major </i>showed reduced photosynthesis and Fv/Fm, increased catalase and ascorbate peroxidase activity, reduced phosphate and nitrate contents in respective treatments. In addition, assessment of root morphological parameters revealed that nutrient deficiencies could lead to higher root densities and increased root to shoot ratios.</p><p>For molecular analysis of transcriptome changes, 24 hours of nutrient starvation exhibited an alteration of 33, 221, and 329 genes for the deficiencies of phosphorus, nitrogen and combined nitrogen and phosphorus, respectively. Our study helped to dissect several novel pathways associated with the vascular system in response to the deficiencies of major macronutrients. </p>

EPHB2, an ephrin receptor (EPH) from receptor tyrosine kinase (RTK) family, is one of the substrates for tissue factor (TF) - coagulation factor VIIa (FVIIa) complex and it is cleaved in its ectodomain. EPHB2 cleavage is important for ephrin receptor (EPH) - ephrin ligand (EFN) signaling and cell repulsion. TF has been reported to be overexpressed in different cancer types such as breast and colorectal cancer (CRC). Furthermore, EPHB2 R155C mutation, at the TF/FVIIa-mediated cleavage site, has been identified as one of the somatic mutation sites in human metastatic CRC. Therefore, the aim of the present work was to characterize the EPHB2 R155C mutation and its effect on the cleavage by TF/FVIIa on EPHB2 in context to CRC. We generated overexpression cell models for EPHB2 wild type (wt) and R155C mutant in human CRC DLD-1 cell line for in vitro compartmentalization assay analysis to demonstrate repulsion event in EPH-EFN signaling. Whereas low endogenous TF expression led to incomplete cleavage of EPHB2 wt protein, stable overexpression of TF resulted in complete cleavage. Moreover, overexpression of TF resulted in reduced compartmentalization in EPHB2 wt cells after FVIIa treatment. Transient expression of TF in EPHB2 wt and R155C cells showed no clear difference in EPHB2 cleavage. Interestingly, it was difficult to obtain similar stable overexpression level of TF in EPHB2 R155C cells compared to EPHB2 wt cells. This may lead to further research in context to the role of TF/FVIIa-mediated EPHB2 cleavage in CRC by the generation of TF overexpression cell lines using lentiviral transduction.

<p>  </p> <p>Down syndrome (DS) is caused by the partial or complete trisomy of human chromosome 21 (Hsa21) and can result in skeletal deficits, including lower bone mineral density (BMD) and increased risk of fracture and osteoporosis or osteopenia earlier than the general population. Mouse models of DS have been developed to understand the genetic mechanisms resulting in these phenotypes, but models differ due to the complex genetic nature of DS and differing genome structures between humans and mice. Ts65Dn mice have been a popular model of DS as they contain ~50% of Hsa21 orthologous genes on a freely segregating minichromosome, but there is speculation that the phenotypes are exaggerated by non-Hsa21 orthologous trisomic genes also present. To address this issue, the Ts66Yah mouse model was developed to remove the non-Hsa21 orthologous trisomic genes. In this study, male and female Ts66Yah mouse femurs were evaluated during bone accrual and peak bone mass to investigate structural differences using micro-computed tomography. Additionally, the role of trisomic <em>Dyrk1a</em>, a Hsa21 gene previously linked to bone deficits in Ts65Dn mice, was evaluated through genetic and pharmacological means in Ts66Yah femurs at postnatal day 36. Ts66Yah mice were found to have little or no trabecular deficits at any age evaluated, but sex-dependent cortical deficits were present at all ages investigated. Reducing <em>Dyrk1a</em> copy number in Ts66Yah mice significantly improved cortical deficits but did not return cortical bone to euploid levels. Pharmacological treatment with DYRK1A inhibitor L21 was confounded by multiple variables, making it difficult to draw conclusions about DYRK1A inhibition in this manner. Overall, these results indicate trabecular deficits associated with Ts65Dn mice may be due to the non-Hsa21 orthologous trisomic genes, and more Hsa21 orthologous trisomic genes are necessary to produce trabecular deficits in DS model mice. As more mouse models of DS are developed, multiple models need to be assessed to accurately define DS-associated phenotypes and test potential treatments.</p>

Argonaute proteins play substantial roles in post-transcriptional regulation of gene expression within RNA interference (RNAi) pathways, making them crucial subjects for research, aimed at understanding their interactions with small non-coding RNAs (ncRNAs) and other RNAi components. This study focuses on investigating these properties of Argonaute proteins, particularly Argonaute protein A (AgnA), in the social amoeba Dictyostelium discoideum that is renowned for its broad genetic toolbox and unique life cycle. While previous studies have examined the disruption of three Argonaute genes (agnB, agnC, agnE) and their effect on mRNA levels and small ncRNA expression, this study extends to agnA gene, which remains less studied. Key questions surrounding the influence of AgnA on the cellular processes such as the cell growth rate, development, gene expression, as well as potential targets and small ncRNA binding, remain unanswered. A well-established approach that could provide the necessary answers is the disruption of the gene through traditional homologous recombination, by insertion of a drug-resistance cassette flanked by homology arms complementary to the target locus. However, the emerging CRISPR/Cas9 gene editing tool on contrary offers straightforward protocols for disruption of gene expression through efficient induction of genomic knockouts, point mutations and deletions. In this study, both approaches were applied in parallel to knockout the agnA gene, enabling comparison of knockout efficiency and further study of the growth rate, development and gene expression in the knockout strains. Moreover, important information regarding the growth patterns of both wild-type and agnE knockout strains were also elucidated, complementing the previous growth rate analyses. The obtained data from this research could provide valuable insights for future studies ofthe RNAi machinery components and particularly the function of Argonaute proteins in D. discoideum.

Åldrande befolkningar är en global utmaning särskilt med ökande incidens av åldersrelateradesjukdomar, särskilt Alzheimers sjukdom (AD). AD är den mest förekommande formen avdemens. Sjukdomen, kännetecknas av kognitiv försämring, med varierande grad avminnesförlust och funktionsnedsättning. Alzheimers patologi involverar ackumulering av β-amyloidpeptider och hyperfosforylerat tauprotein,vilka bidrar till sjukdomens progression. Östrogen samt östrogenreceptorerna påverkarmånga kroppsfunktioner och är särskilt viktiga för neuroprotektion och reglering av genuttryck.Trots kunskapsframsteg är mekanismerna bakom könsskillnader i AD och östrogenets effekterinte helt förstådda, vilket understryker behovet av vidare forskning för att utveckla effektivabehandlingar och förstå sjukdomens underliggande biologi. Syftet med denna studie är att djupare förstå östrogens roll i Alzheimers sjukdom, samt attundersöka utveckling, respektive förbättring av AD beroende på östrogens nivåer i kroppen.För att uppnå syftet, gjordes en systematisk litteratursökning på internationella databaser.Artiklarna som inkluderas i studien granskades och dess relevans bedömdes med noggrannhetvia urvals steg. Endast relevanta artiklar som uppfyller inklusionskraven inkluderades för attbesvara syftet och frågeställningen. Det visades att behandling med östradiol förbättrade minnet hos AD-musmodeller. E2-behandlade möss uppvisade lägre nivåer av β-amyloid plack och minskad tau-fosforyleringjämfört med obehandlade AD-möss. Långvarig hormonbehandling, särskilt hos kvinnor sompåbörjar behandlingen vid en yngre ålder, kan öka risken för Alzheimers sjukdom genom ettöverskott av östrogen, vilket belyser östrogenets komplexa roll i sjukdomens patogenes ochbehandling. Östrogenreceptorerna spelar en roll i regleringen av tau-fosforylering, där ERαöveruttryck ökade tau-fosforyleringen och ERβ överuttryck minskade den. Effekten avöstrogenbehandling på APOE-genotypen i möss visade genotypberoende effekt. Östrogenerbjuder en potentiellt skyddande roll mot Alzheimers sjukdom men effekterna är beroende avindividuella och genetiska faktorer. Resultaten indikerar att östrogen har en potentiellskyddande effekt mot AD genom att modulera β-amyloid och tau-fosforylering samt genom attfrämja neurogenes. Dessa fynd understryker östrogens betydelse som ett potentiellt terapeutisktmål för AD, särskilt med tanke på de genetiska och hormonella faktorer som bidrar tillsjukdomsutvecklingen. Resultaten understryker vikten av försiktighet vidhormonersättningsterapi och behovet av ytterligare forskning för att förstå de genetiska ochhormonella faktorernas inverkan på risken för Alzheimers.