Persistence and Sexual Dimorphism of Gut Dysbiosis and Pathobiome after Sepsis and Trauma.

OBJECTIVE: To evaluate the persistence of intestinal microbiome dysbiosis and gut-plasma metabolomic perturbations following severe trauma or sepsis weeks after admission in patients experiencing chronic critical illness (CCI). SUMMARY: Trauma and sepsis can lead to gut dysbiosis and alterations in the plasma and fecal metabolome. However, the impact of these perturbations and correlations between gut dysbiosis and the plasma metabolome in chronic critical illness have not been studied. METHODS: A prospective observational cohort study was performed with healthy subjects, severe trauma patients, patients with sepsis residing in an intensive care unit (ICU) for 2-3 weeks. A high-throughput multi-omics approach was utilized to evaluate the gut microbial and gut-plasma metabolite responses in critically ill trauma and sepsis patients 14-21 days after ICU admission. RESULTS: Patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with significant alterations and specific pathobiome patterns in the microbiota composition compared to healthy subjects. Further subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts. Sex-specific changes in fecal metabolites were also observed after trauma and sepsis, while plasma metabolite changes were similar in both males and females. CONCLUSIONS: Dysbiosis induced by trauma and sepsis persists up to 14-21 days after onset and is sex-specific, underscoring the implication of pathobiome and entero-septic microbial-metabolite perturbations in post-sepsis and post-trauma CCI. This indicates resilience to infection or injury in females' microbiome and should inform and facilitate future precision/personalized medicine strategies in the intensive care unit.

Gut mycobiome dysbiosis after sepsis and trauma.

BACKGROUND: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. METHODS: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. RESULTS: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. CONCLUSIONS: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection.

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function.

BACKGROUND AND AIM: The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. METHODS: Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP­ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. RESULTS: Our studies demonstrated that HFD in Jnk3-/- lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. CONCLUSIONS: Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.

Automated Isoform Diversity Detector (AIDD): a pipeline for investigating transcriptome diversity of RNA-seq data.

BACKGROUND: As the number of RNA-seq datasets that become available to explore transcriptome diversity increases, so does the need for easy-to-use comprehensive computational workflows. Many available tools facilitate analyses of one of the two major mechanisms of transcriptome diversity, namely, differential expression of isoforms due to alternative splicing, while the second major mechanism-RNA editing due to post-transcriptional changes of individual nucleotides-remains under-appreciated. Both these mechanisms play an essential role in physiological and diseases processes, including cancer and neurological disorders. However, elucidation of RNA editing events at transcriptome-wide level requires increasingly complex computational tools, in turn resulting in a steep entrance barrier for labs who are interested in high-throughput variant calling applications on a large scale but lack the manpower and/or computational expertise. RESULTS: Here we present an easy-to-use, fully automated, computational pipeline (Automated Isoform Diversity Detector, AIDD) that contains open source tools for various tasks needed to map transcriptome diversity, including RNA editing events. To facilitate reproducibility and avoid system dependencies, the pipeline is contained within a pre-configured VirtualBox environment. The analytical tasks and format conversions are accomplished via a set of automated scripts that enable the user to go from a set of raw data, such as fastq files, to publication-ready results and figures in one step. A publicly available dataset of Zika virus-infected neural progenitor cells is used to illustrate AIDD's capabilities. CONCLUSIONS: AIDD pipeline offers a user-friendly interface for comprehensive and reproducible RNA-seq analyses. Among unique features of AIDD are its ability to infer RNA editing patterns, including ADAR editing, and inclusion of Guttman scale patterns for time series analysis of such editing landscapes. AIDD-based results show importance of diversity of ADAR isoforms, key RNA editing enzymes linked with the innate immune system and viral infections. These findings offer insights into the potential role of ADAR editing dysregulation in the disease mechanisms, including those of congenital Zika syndrome. Because of its automated all-inclusive features, AIDD pipeline enables even a novice user to easily explore common mechanisms of transcriptome diversity, including RNA editing landscapes.

High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents.

Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce ß-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age.

Luteinizing hormone downregulation but not estrogen replacement improves ovariectomy-associated cognition and spine density loss independently of treatment onset timing.

Age-related changes in reproductive hormone levels are a well-known risk factor for the development of cognitive dysfunction and dementia in women. We and others have shown an important contribution of gonadotropins in this process. Lowering serum gonadotropin levels is able to rescue cognitive function in Alzheimer's disease and menopause models, but whether this is time-dependent and the exact mechanism through which gonadotropins regulate cognitive function is unknown. We show that pharmacologically lowering serum levels of luteinizing hormone lead to cognitive improvement immediately after ovariectomy and with a 4month interval after ovariectomy, when the benefits of 17ß-estradiol are known to disappear in rodents. Importantly, we show that these improvements are associated with spine density changes at both time points. These findings suggest a role of luteinizing hormone in learning and memory and neuroplasticity processes as well as provide an alternative therapeutic strategy of menopause associated cognitive loss.

Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by decreasing anandamide levels and by activating the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) in the brain.

Endocannabinoids modulate multiple behaviors, including learning and memory. We show that the endocannabinoid anandamide (AEA) can alter neuronal cell function both through its established role in activation of the G-protein-coupled receptor CB1, and by serving as a precursor for a potent agonist of the nuclear receptor PPARß/δ, in turn up-regulating multiple cognition-associated genes. We show further that the fatty acid-binding protein FABP5 controls both of these functions in vivo. FABP5 both promotes the hydrolysis of AEA into arachidonic acid and thus reduces brain endocannabinoid levels, and directly shuttles arachidonic acid to the nucleus where it delivers it to PPARß/δ, enabling its activation. In accordance, ablation of FABP5 in mice results in excess accumulation of AEA, abolishes PPARß/δ activation in the brain, and markedly impairs hippocampus-based learning and memory. The data indicate that, by controlling anandamide disposition and activities, FABP5 plays a key role in regulating hippocampal cognitive function.

Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease.

The present study had focused on the behavioral phenotype and gene expression profile of molecules related to insulin receptor signaling in the hippocampus of 3 and 6 month-old APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease (AD). Elevated levels of the insoluble Aß (1-42) were detected in the brain extracts of the transgenic animals as early as 3 months of age, prior to the Aß plaque formation (pre-plaque stage). By the early plaque stage (6 months) both the soluble and insoluble Aß (1-40) and Aß (1-42) peptides were detectable. We studied the expression of genes related to memory function (Arc, Fos), insulin signaling, including insulin receptor (Insr), Irs1 and Irs2, as well as genes involved in insulin growth factor pathways, such as Igf1, Igf2, Igfr and Igfbp2. We also examined the expression and protein levels of key molecules related to energy metabolism (PGC1-α, and AMPK) and mitochondrial functionality (OXPHOS, TFAM, NRF1 and NRF2). 6 month-old APP/PS1 mice demonstrated impaired cognitive ability, were glucose intolerant and showed a significant reduction in hippocampal Insr and Irs2 transcripts. Further observations also suggest alterations in key cellular energy sensors that regulate the activities of a number of metabolic enzymes through phosphorylation, such as a decrease in the Prkaa2 mRNA levels and in the pAMPK (Thr172)/Total APMK ratio. Moreover, mRNA and protein analysis reveals a significant downregulation of genes essential for mitochondrial replication and respiratory function, including PGC-1α in hippocampal extracts of APP/PS1 mice, compared to age-matched wild-type controls at 3 and 6 months of age. Overall, the findings of this study show early alterations in genes involved in insulin and energy metabolism pathways in an APP/PS1 model of AD. These changes affect the activity of key molecules like NRF1 and PGC-1α, which are involved in mitochondrial biogenesis. Our results reinforce the hypothesis that the impairments in both insulin signaling and energy metabolism precede the development of AD amyloidogenesis.

Luteinizing hormone: Evidence for direct action in the CNS.

This article is part of a Special Issue "SBN 2014". Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic-pituitary-gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.

Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice.

Development of Alzheimer's disease (AD) has been linked to the de-regulation of estrogen and gonadotropins such as luteinizing hormone (LH). In this study, we found increases in AD pathology in the hippocampi of aged female 3xTg AD mice after ovariectomy that were unable to be reduced by estrogen therapy or down-regulation of serum LH levels. Despite the lack of effect of these treatments on AD pathology, down-regulation of serum LH but not estrogen improved factors associated with neuronal plasticity such as spatial memory, inhibition of glycogen synthase kinase-3 beta, expression of beta-catenin, and brain-derived neurotrophic factor transcription. Contrasting previous studies in younger mice, estrogen replacement was not able to rescue behavioral deficits, reduced glycogen synthase kinase-3 beta inhibition and increased hippocampal phosphorylation of tau. Of critical importance, serum LH was negatively correlated with brain LH in regions associated with spatial memory, and increases in brain LH correlated with cognitive improvement. This paralleled changes in human female AD brains which showed a significant reduction in brain LH mRNA compared to healthy age- and PMI-matched controls. Taken together, these findings should promote further research into the LH-dependent mechanisms associated with AD cognitive deficits as well as the effects of estrogen within the aged brain. In the aged triple transgenic Alzheimer's disease (AD) mouse model (3xAD-Tg), estrogen replacement after ovariectomy does not improve cognitive function, increases phosphorylated Tau levels and decreases inhibition of GSK3 beta. Luprolide acetate rescues ovariectomy-dependent cognitive function, increases signaling events associated with synaptic plasticity including GSK3 beta inhibition, but does not alter AD pathology. In the human AD female brain, luteinizing hormone (LH) mRNA levels are reduced. In the 3XAD-tg model, brain LH protein levels are reduced by ovariectomy and normalized by leuprolide acetate treatment. These treatment-dependent normalization of LH positively correlates with markers of neuroplasticity and cognitive improvement.

Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-ß. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.

LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.

The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in the pathogenesis of PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased mitochondrial dynamin-like protein (DLP1, also known as DRP1), a fission protein, which was further exacerbated by expression of PD-associated mutants (R1441C or G2019S) in both SH-SY5Y and differentiated primary cortical neurons. We also found that LRRK2 interacted with DLP1, and LRRK2-DLP1 interaction was enhanced by PD-associated mutations that probably results in increased mitochondrial DLP1 levels. Co-expression of dominant-negative DLP1 K38A or WT Mfn2 blocked LRRK2-induced mitochondrial fragmentation, mitochondrial dysfunction and neuronal toxicity. Importantly, mitochondrial fragmentation and dysfunction were not observed in cells expressing either GTP-binding deficient mutant LRRK2 K1347A or kinase-dead mutant D1994A which has minimal interaction with DLP1 and did not increase the mitochondrial DLP1 level. We concluded that LRRK2 regulates mitochondrial dynamics by increasing mitochondrial DLP1 through its direct interaction with DLP1, and LRRK2 kinase activity plays a critical role in this process.

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.

Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128.

JOURNAL/nrgr/04.03/01300535-202419110-00033/figure1/v/2024-03-08T184507Z/r/image-tiff Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer's disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer's disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3' untranslated region (3'-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128.

Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer's Disease.

BACKGROUND: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer's disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. OBJECTIVE: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. METHODS: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. RESULTS: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. CONCLUSION: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

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.

Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease.

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells over-expressing familial AD-causing amyloid precursor protein (APP) mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α)-nuclear respiratory factor (NRF)-mitochondrial transcription factor A pathway. Expression levels of PGC-1α, NRF 1, NRF 2, and mitochondrial transcription factor A were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, over-expression of PGC-1α could completely rescue while knockdown of PGC-1α could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe-induced mitochondrial deficits. We further demonstrated that reduced expression of p-CREB and PGC-1α in APPswe M17 cells could be rescued by cAMP in a dose-dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC-1α expression in APPswe M17 cells. Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD.

Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome.

Fragile X syndrome (FXS) is a developmental disorder caused by the loss of Fragile X Mental Retardation 1 (FMR1) gene function because of a CGG repeat expansion (> 200 repeats) in the gene. The molecular mechanism(s) linking loss of FMR1 function to the molecular pathology and cognitive/behavioral disability remain unclear. Given the critical role of extracellular signal-regulated kinase (ERK) in synaptic plasticity and neurodevelopment, a number of recent studies have investigated ERK phosphorylation under basal conditions or upon mGluR-induction using neuronal and peripheral tissues from Fmr1 knockout mice and peripheral tissues from FXS patients. However, these reports have presented conflicting results. The current study is the first to focus on the levels of ERK phosphorylation in brain tissue from human FXS patients. In both human brain tissue and brain tissue from Fmr1 knockout mice there was significantly increased phosphorylation of MEK1/2 and ERK. Indeed, treating Fmr1 knockout mice with the MEK1/2 inhibitor SL327 abrogated audiogenic seizure activity, a feature of the Fmr1 knockout mice that replicates the symptom in patients with FXS. These findings suggest that activation of the ERK pathway results in some cardinal cognitive and clinical features in FXS patients and likely have profound translational implications.

Amylin Pharmacology in Alzheimer's Disease Pathogenesis and Treatment.

The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer's disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer's disease. The traditional "gain of toxic function" properties assigned to amyloid proteins are, however, contrasted by several reports highlighting neuroprotective effects of amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address the paradoxical nature of this hormone's signaling in the context of AD pathogenesis.