Genome-wide profiling of prime editor off-target sites in vitro and in vivo using PE-tag.

Prime editors have a broad range of potential research and clinical applications. However, methods to delineate their genome-wide editing activities have generally relied on indirect genome-wide editing assessments or the computational prediction of near-cognate sequences. Here we describe a genome-wide approach for the identification of potential prime editor off-target sites, which we call PE-tag. This method relies on the attachment or insertion of an amplification tag at sites of prime editor activity to allow their identification. PE-tag enables genome-wide profiling of off-target sites in vitro using extracted genomic DNA, in mammalian cell lines and in the adult mouse liver. PE-tag components can be delivered in a variety of formats for off-target site detection. Our studies are consistent with the high specificity previously described for prime editor systems, but we find that off-target editing rates are influenced by prime editing guide RNA design. PE-tag represents an accessible, rapid and sensitive approach for the genome-wide identification of prime editor activity and the evaluation of prime editor safety.

Precise therapeutic gene correction by a simple nuclease-induced double-stranded break.

Current programmable nuclease-based methods (for example, CRISPR-Cas9) for the precise correction of a disease-causing genetic mutation harness the homology-directed repair pathway. However, this repair process requires the co-delivery of an exogenous DNA donor to recode the sequence and can be inefficient in many cell types. Here we show that disease-causing frameshift mutations that result from microduplications can be efficiently reverted to the wild-type sequence simply by generating a DNA double-stranded break near the centre of the duplication. We demonstrate this in patient-derived cell lines for two diseases: limb-girdle muscular dystrophy type 2G (LGMD2G)1 and Hermansky-Pudlak syndrome type 1 (HPS1)2. Clonal analysis of inducible pluripotent stem (iPS) cells from the LGMD2G cell line, which contains a mutation in TCAP, treated with the Streptococcus pyogenes Cas9 (SpCas9) nuclease revealed that about 80% contained at least one wild-type TCAP allele; this correction also restored TCAP expression in LGMD2G iPS cell-derived myotubes. SpCas9 also efficiently corrected the genotype of an HPS1 patient-derived B-lymphoblastoid cell line. Inhibition of polyADP-ribose polymerase 1 (PARP-1) suppressed the nuclease-mediated collapse of the microduplication to the wild-type sequence, confirming that precise correction is mediated by the microhomology-mediated end joining (MMEJ) pathway. Analysis of editing by SpCas9 and Lachnospiraceae bacterium ND2006 Cas12a (LbCas12a) at non-pathogenic 4-36-base-pair microduplications within the genome indicates that the correction strategy is broadly applicable to a wide range of microduplication lengths and can be initiated by a variety of nucleases. The simplicity, reliability and efficacy of this MMEJ-based therapeutic strategy should permit the development of nuclease-based gene correction therapies for a variety of diseases that are associated with microduplications.

Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.

BACKGROUND: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood. OBJECTIVES: This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis. METHODS: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing. RESULTS: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization. CONCLUSIONS: Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.

Enhanced Cas12a editing in mammalian cells and zebrafish.

Type V CRISPR-Cas12a systems provide an alternate nuclease platform to Cas9, with potential advantages for specific genome editing applications. Here we describe improvements to the Cas12a system that facilitate efficient targeted mutagenesis in mammalian cells and zebrafish embryos. We show that engineered variants of Cas12a with two different nuclear localization sequences (NLS) on the C terminus provide increased editing efficiency in mammalian cells. Additionally, we find that pre-crRNAs comprising a full-length direct repeat (full-DR-crRNA) sequence with specific stem-loop G-C base substitutions exhibit increased editing efficiencies compared with the standard mature crRNA framework. Finally, we demonstrate in zebrafish embryos that the improved LbCas12a and FnoCas12a nucleases in combination with these modified crRNAs display high mutagenesis efficiencies and low toxicity when delivered as ribonucleoprotein complexes at high concentration. Together, these results define a set of enhanced Cas12a components with broad utility in vertebrate systems.

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.

Inter-Individual Variation in Response to Estrogen in Human Breast Explants.

Exposure to estrogen is strongly associated with increased breast cancer risk. While all women are exposed to estrogen, only 12% are expected to develop breast cancer during their lifetime. These women may be more sensitive to estrogen, as rodent models have demonstrated variability in estrogen sensitivity. Our objective was to determine individual variation in expression of estrogen receptor (ER) and estrogen-induced responses in the normal human breast. Human breast tissue from female donors undergoing reduction mammoplasty surgery were collected for microarray analysis of ER expression. To examine estrogen-induced responses, breast tissue from 23 female donors were cultured ex- vivo in basal or 10 nM 17ß-estradiol (E2) media for 4 days. Expression of ER genes (ESR1 and ESR2) increased significantly with age. E2 induced consistent increases in global gene transcription, but expression of target genes AREG, PGR, and TGFß2 increased significantly only in explants from nulliparous women. E2-treatment did not induce consistent changes in proliferation or radiation induced apoptosis. Responses to estrogen are highly variable among women and not associated with levels of ER expression, suggesting differences in intracellular signaling among individuals. The differences in sensitivity to E2-stimulated responses may contribute to variation in risk of breast cancer.

Alternative splicing is highly variable among Daphnia pulex lineages in response to acute copper exposure.

BACKGROUND: Despite being one of the primary mechanisms of gene expression regulation in eukaryotes, alternative splicing is often overlooked in ecotoxicogenomic studies. The process of alternative splicing facilitates the production of multiple mRNA isoforms from a single gene thereby greatly increasing the diversity of the transcriptome and proteome. This process can be important in enabling the organism to cope with stressful conditions. Accurate identification of splice sites using RNA sequencing requires alignment to independent exonic positions within the genome, presenting bioinformatic challenges, particularly when using short read data. Although technological advances allow for the detection of splicing patterns on a genome-wide scale, very little is known about the extent of intraspecies variation in splicing patterns, particularly in response to environmental stressors. In this study, we used RNA-sequencing to study the molecular responses to acute copper exposure in three lineages of Daphnia pulex by focusing on the contribution of alternative splicing in addition to gene expression responses. RESULTS: By comparing the overall gene expression and splicing patterns among all 15 copper-exposed samples and 6 controls, we identified 588 differentially expressed (DE) genes and 16 differentially spliced (DS) genes. Most of the DS genes (13) were not found to be DE, suggesting unique transcriptional regulation in response to copper that went unnoticed with conventional DE analysis. To understand the influence of genetic background on gene expression and alternative splicing responses to Cu, each of the three lineages was analyzed separately. In contrast to the overall analysis, each lineage had a higher proportion of unique DS genes than DE genes suggesting that genetic background has a larger influence on DS than on DE. Gene Ontology analysis revealed that some pathways involved in stress response were jointly regulated by DS and DE genes while others were regulated by only transcription or only splicing. CONCLUSIONS: Our findings suggest an important role for alternative splicing in shaping transcriptome diversity in response to metal exposure in Daphnia, highlighting the importance of integrating splicing analyses with gene expression surveys to characterize molecular pathways in evolutionary and environmental studies.

Partial DNA-guided Cas9 enables genome editing with reduced off-target activity.

CRISPR-Cas9 is a versatile RNA-guided genome editing tool. Here we demonstrate that partial replacement of RNA nucleotides with DNA nucleotides in CRISPR RNA (crRNA) enables efficient gene editing in human cells. This strategy of partial DNA replacement retains on-target activity when used with both crRNA and sgRNA, as well as with multiple guide sequences. Partial DNA replacement also works for crRNA of Cpf1, another CRISPR system. We find that partial DNA replacement in the guide sequence significantly reduces off-target genome editing through focused analysis of off-target cleavage, measurement of mismatch tolerance and genome-wide profiling of off-target sites. Using the structure of the Cas9-sgRNA complex as a guide, the majority of the 3' end of crRNA can be replaced with DNA nucleotide, and the 5 - and 3'-DNA-replaced crRNA enables efficient genome editing. Cas9 guided by a DNA-RNA chimera may provide a generalized strategy to reduce both the cost and the off-target genome editing in human cells.

Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018.

Growing evidence suggests receipt of live-attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2-day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post-SOT. For consideration of VV and MMR post-transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post-SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell-depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in-depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of "low-level" immune suppression as defined in the document.

Non-polio Enterovirus detection with acute flaccid paralysis: A systematic review.

Acute flaccid paralysis (AFP), as defined by the World Health Organization (WHO), is characterized by an acute onset of limb weakness. In the post-polio era, other enterovirus (EV) serotypes associated with AFP may become more prominent. This study aims to collate the data on the non-polio enteroviruses (NPEV) associated with AFP. A systematic review of published case reports, case series, and surveillance studies of AFP from 1960 through 2017 was undertaken. Data were collected including the country of the study, number of specimens positive for NPEV and available clinical data. The majority of studies originated from Asia. In surveillance studies, EV 71 (a serotype of Enterovirus A) was the most commonly detected serotype with AFP, followed by Enterovirus B serotype echovirus 11 and then Enterovirus B serotype echovirus 11. In case studies and case reports, EV 71 and EV 68 (a serotype of Enterovirus D), were the most commonly detected NPEV. As poliovirus eradication continues, there is a need to ensure that AFP surveillance will also detect other potentially vaccine preventable viruses.

A risk-stratified approach to cytomegalovirus prevention in pediatric solid organ transplant recipients.

Optimal strategies to prevent cytomegalovirus (CMV) disease following pediatric solid organ transplantation remain controversial. The purpose of this study was to review the outcomes of a risk-stratified strategy that uses a hybrid or prophylactic strategy for donor (D)+ recipient (R)- patients, a preemptive strategy for D+R+/D-R+, and clinical follow-up alone for D-R+ patients. A retrospective chart review was undertaken at the Stollery Children's Hospital in Edmonton, Alberta for pediatric solid organ transplants 2004 through 2010. Transplants were risk-stratified according to D/R CMV serostatus, organ group, and type of induction or rejection immunosuppression. The incidence of DNAemia and CMV disease and adverse effects from prophylaxis were analyzed. The study included 197 recipients. CMV DNAemia was detected in 49 of 197 recipients (24.8%), and CMV disease occurred in eight of 197 (4%) of which all but one were D+R-. All recovered. Seventeen of 142 recipients who received prophylaxis (12%) had hematologic toxicity. No other toxicities were identified. In conclusion, A risk-stratified approach resulted in very low rates of CMV disease with minimal adverse effects. Lowering the dosage rather than stopping antivirals in the face of neutropenia has the potential to further lower the rate of CMV disease.

A Rare Presentation of Delusional Parasitosis With Koro-Like Syndrome.

Delusional parasitosis (DP) with Koro-like syndrome poses a complex clinical challenge, demanding a comprehensive and empathetic approach from healthcare professionals. This exceptional combination of fixed beliefs about infestation and experiences of genital retraction can profoundly impact patients' well-being and daily functioning. The associated stigma and misconceptions further compound the difficulties faced by individuals struggling with these co-occurring conditions. Given the rarity of encountering both conditions simultaneously, navigating the diagnosis and treatment of delusional parasitosis with Koro-like syndrome requires a thorough understanding of its multifaceted nature. Embracing a holistic strategy encompassing psychoeducation, psychotherapy, and pharmacological interventions is essential for effectively addressing these dual conditions.

Unexpected Cataract Formation Following Valproate Treatment: A Case Report.

Valproic acid (VPA), or sodium valproate, is a frequently prescribed medication for many psychiatric conditions, notably for the management of bipolar affective disorder. While its common side effects are well known and thoroughly documented in medical literature, the occurrence of cataracts as a side effect is exceedingly rare. There is evidence of cataract formation with long-term use of VPA in a few studies. Recognizing this potential adverse effect is crucial. It is important to recommend that patients undergo regular eye examinations if they experience any visual disturbances or as a preventative measure to ensure effective management. This case report examines the unusual occurrence of cataract development associated with valproate use.

Therapeutic benefits of central LH receptor agonism in the APP/PS1 AD model involve trophic and immune regulation and are reproductive status dependent.

The mechanisms that underly reproductive hormone effects on cognition, neuronal plasticity, and AD risk, particularly in relation to gonadotropin LH receptor (LHCGR) signaling, remain poorly understood. To address this gap in knowledge and clarify the impact of circulating steroid hormones on the therapeutic effects of CNS LHCGR activation, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV) and evaluated functional, structural, plasticity-related signaling cascades, Aß pathology, and transcriptome differences in reproductively intact and ovariectomized (OVX) APP/PS1 AD female mice. Here we demonstrate that CNS hCG delivery restored function to wild-type levels only in OVX APP/PS1 mice. Spine density was increased in all hCG treated groups independently of reproductive status. Notably, increases in BDNF signaling and cognition, were selectively upregulated only in the OVX hCG-treated group. RNA sequencing analyses identified a significant increase in peripheral myeloid and pro-inflammatory genes within the hippocampi of the OVX group that were completely reversed by hCG treatment, identifying a potential mechanism underlying the selective therapeutic effect of LHCGR activation. Interestingly, in intact mice, hCG administration mimicked the effects of gonadectomy. Together, our findings indicate that CNS LHCGR agonism in the post-menopausal context is beneficial through trophic and immune mechanisms. Our findings also underscore the presence of a steroid-LHCGR mechanistic interaction that is unexplored yet potentially meaningful to fully understand "post-menopausal" brain function and CNS hormone treatment response.

Long non-coding RNAs mediate fish gene expression in response to ocean acidification.

The majority of the transcribed genome does not have coding potential but these non-coding transcripts play crucial roles in transcriptional and post-transcriptional regulation of protein-coding genes. Regulation of gene expression is important in shaping an organism's response to environmental changes, ultimately impacting their survival and persistence as population or species face global change. However, the roles of long non-coding RNAs (lncRNAs), when confronted with environmental changes, remain largely unclear. To explore the potential role of lncRNAs in fish exposed to ocean acidification (OA), we analyzed publicly available brain RNA-seq data from a coral reef fish Acanthochromis polyacanthus. We annotated the lncRNAs in its genome and examined the expression changes of intergenic lncRNAs (lincRNAs) between A. polyacanthus samples from a natural CO2 seep and a nearby control site. We identified 4728 lncRNAs, including 3272 lincRNAs in this species. Remarkably, 93.03% of these lincRNAs were species-specific. Among the 125 highly expressed lincRNAs and 403 differentially expressed lincRNAs in response to elevated CO2, we observed that lincRNAs were either neighboring or potentially trans-regulating differentially expressed coding genes associated with pH regulation, neural signal transduction, and ion transport, which are known to be important in the response to OA in fish. In summary, lncRNAs may facilitate fish acclimation and mediate the responses of fish to OA by modulating the expression of crucial coding genes, which offers insight into the regulatory mechanisms underlying fish responses to environmental changes.

Brain transcriptome of gobies inhabiting natural CO2 seeps reveal acclimation strategies to long-term acidification.

Ocean acidification (OA) is known to affect the physiology, survival, behaviour and fitness of various fish species with repercussions at the population, community and ecosystem levels. Some fish species, however, seem to acclimate rapidly to OA conditions and even thrive in acidified environments. The molecular mechanisms that enable species to successfully inhabit high CO2 environments have not been fully elucidated especially in wild fish populations. Here, we used the natural CO2 seep in Vulcano Island, Italy to study the effects of elevated CO2 exposure on the brain transcriptome of the anemone goby, a species with high population density in the CO2 seep and investigate their potential for acclimation. Compared to fish from environments with ambient CO2, gobies living in the CO2 seep showed differences in the expression of transcripts involved in ion transport and pH homeostasis, cellular stress, immune response, circadian rhythm and metabolism. We also found evidence of potential adaptive mechanisms to restore the functioning of GABAergic pathways, whose activity can be affected by exposure to elevated CO2 levels. Our findings indicate that gobies living in the CO2 seep may be capable of mitigating CO2-induced oxidative stress and maintaining physiological pH while meeting the consequent increased energetic costs. The conspicuous difference in the expression of core circadian rhythm transcripts could provide an adaptive advantage by increasing the flexibility of physiological processes in elevated CO2 conditions thereby facilitating acclimation. Our results show potential molecular processes of acclimation to elevated CO2 in gobies enabling them to thrive in the acidified waters of Vulcano Island.

Comparative Assessment of the Periodontal Findings in Child Subjects With a Normal Body Mass Index and in Obese Subjects.

BACKGROUND: Obesity in children is a concerning issue affecting a large population globally. Obesity and overweight are risk factors for various medical conditions, including periodontal diseases, hypertension, cerebrovascular disease, cardiovascular disease, and/or diabetes. AIM: The study aimed to comparatively assess the periodontal findings in child subjects with a normal BMI and in obese subjects. METHODS: The present observational study aimed to comparatively assess 216 school-going child subjects that were divided into two groups: non-obese (BMI<25) and obese, with BMI≥25 having equal gender distribution. In both groups, clinical attachment loss (CAL), probing depth (PD), and bleeding on probing (BOP) were assessed along with a questionnaire on oral hygiene and dietary habits. The data gathered were statistically analysed. RESULTS: The study results showed that in obese subjects, significantly higher values were seen for probing depth, bleeding on probing, and plaque index compared to non-obese subjects with p<0.05. However, no significant difference was noted in the CAL of obese and non-obese subjects (p>0.05). CONCLUSION: The periodontal status is compromised in obese subjects with higher values of probing depth, bleeding on probing, and plaque index compared to child subjects with normal weight. The level of CAL does not differ significantly between obese and non-obese child subjects.

A Cross-Sectional Study to Analyze the Correlation Between Alexithymia and Dental Neglect in Persons Pursuing Dental Care.

Background Alexithymia is a personality trait involving difficulties in emotional regulation (difficulties in identifying feelings, difficulties in describing feelings, and externally oriented thinking). It has a negative impact on health as it evokes poor personal hygiene, poor nutrition, and unhealthy behaviors in affected subjects. Identifying alexithymia in the dental setup is vital as it can compromise the patient-dentist relationship, especially in subjects neglecting oral hygiene. Aims The present study aimed to establish an association between alexithymia and dental neglect among adult subjects seeking dental care by using Dental Neglect Scale (DNS), and alexithymia was assessed on the 20-item Toronto Alexithymia Scale (TAS-20). Methods The present cross-sectional survey study included adult subjects of age 20 years or more. For all included participants, a structured questionnaire was given to assess dental neglect on demographic profile, six items of the DNS, and alexithymia was assessed on the 20-item TAS-20. The collected data were analyzed using a Chi-square test keeping significance at the p-value of <0.05. Results In 534 adult subjects, females had high scores for both TAS-20 and DNS along with their related factors. With higher education and increasing age, a significant increase in the mean TAS-20 scores and mean DNS scores was seen in the study participants (high mean DNS scores in females (19.55±3.98) compared to male subjects 19.36±4.34). TAS-20 scores were higher in females (59.31±10.78), factor 1 (DIF) (19.54±5.54), factor 2 (DDF) (15.46±4.05), and factor 3 (EOT) (24.34±4.64). Conclusion The present study, considering its limitations, concludes that there is no association between dental neglect and alexithymia in adult subjects seeking dental care. However, higher DNS and TAS-20 scores are seen in females showing them have difficult descriptions and identification of feelings in dental set-up increasing dental neglect among them.

The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice.

Activation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, Aß pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering Aß pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the "menopausal" AD brain.