Female Alzheimer's Disease Research Articles

Lifespan of male and female APP/PS1 and APPNL-F/NL-F mouse models of Alzheimer's disease.

Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between within genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports sexual dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus, which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aβ and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated.

Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer’s disease

BackgroundAmyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer’s disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD.ResultsImmunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model.ConclusionAged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

Detection of sex-specific glutamate changes in subregions of hippocampus in an early-stage Alzheimer's disease mouse model using GluCEST MRI.

Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high-resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex-specific manner. Eight-month-old male and female AD mice harboring mutant amyloid precursor protein (APPNL-F/NL-F: n = 36) and wild-type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy (1H-MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner. GluCEST measurements revealed significant (p≤0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73±2.12%), hippocampus (11.29±2.41%), and hippocampal fimbriae (19.15±2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22±2.33%; p = 0.01) was also observed in 1H-MRS. GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism. Glutamate levels were monitored in different brain regions of early-stage Alzheimer's disease (AD) and wild-type male and female mice using glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex-specific glutamate changes in hippocampal sub-regions using high-resolution GluCEST MRI.

Abstract P132: Sex Differences in Cerebrovascular Dysfunction in the APP/PS1 TgF344-AD Rat Model of Alzheimer's Disease

Alzheimer's Disease (AD) is the primary cause of dementia and is characterized by extracellular beta-amyloid plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles in the brain. Emerging evidence suggests that cerebrovascular dysfunction is associated with AD. Although two-thirds of AD patients are female, sex differences in transgenic AD models have been largely ignored. The present study investigated sex differences in cerebrovascular dysfunction and potential mechanisms in AD using a TgF344-AD rat model. The APP/PS1 TgF344-AD (AD) rats serve as a preferred model to study AD since they recapitulate the complete repertoire of AD-like pathologies in humans. We previously longitudinally characterized cerebral hemodynamics in male TgF344 AD rats at 3, 4, 6, and 14 months, and reported that 4-month-old AD males displayed early signs of impaired cerebral blood flow (CBF) autoregulation and reduced functional hyperemia, two months earlier than memory loss, which was co-occurred with the appearance of plaques. These deficits progressed with advancing age. The present study used 13-14 months of female TgF344-AD (AD) and F344 (WT) rats. We found that AD females also displayed impaired learning and memory function in the eight-arm swim and open field tests as seen in males. Amyloid plaques were prominent in the hippocampus and cortex of female AD brains at a similar level in males, while no plaques were observed in WT brains. Functional hyperemic responses to whisker stimulation were markedly impaired in female AD rats. Further, we found evidence of astrocyte activation and microgliosis in female AD brains using immunohistochemistry and western blots. The astrocytes and microglial activation formed clusters around amyloid plaques. The direct contact between astrocytic endfeet and penetrating arterioles was markedly reduced in AD animals. Moreover, the blood-brain barrier (BBB) was disrupted in AD animals as the tight junction marker ZO1 was significantly reduced in AD brains. These results demonstrate cerebrovascular dysfunction contributes to loss of cognitive function in both male and female APP/PS1 TgF344-AD rats and is associated with impaired functional hyperemia, loss of astrocytic endfeet on penetrating arterioles, BBB breakdown, neuroinflammation related to amyloid plaques. They also indicate that the female TgF344-AD rat is appropriate for studying age-related influences of sex hormones on AD.

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms. To gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects. Female APP/PS1 mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos+ revealed changes in regional correlations and overall network connectivity in APP/PS1 mice. Sex-specific eYFP+/c-Fos+ changes were observed; female APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in dorsal CA3 (dCA3), while male APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects. While future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that there are sex differences in AD network dysfunction, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach.

Ovariectomy exacerbates the disturbance of excitation- inhibition balance in the brain of APP/PS-1/tau mice.

The prevalence of Alzheimer's disease (AD) is significantly gender-differentiated, with the number of female AD patients far exceeding that of males, accounting for two-thirds of the total prevalence. Although postmenopausal AD mice have been shown to have more prominent pathologic features and memory impairments than normal AD mice, the relevant molecular mechanisms leading to these outcomes have not been well elucidated. In the present study, we used the disturbance of excitation-inhibition balance in the postmenopausal brain as an entry point to explore the link between estrogen deficiency, disorders of the glutamatergic-GABAergic nervous system, and memory impairment. Wild-type (WT) mice and APP/PS1/tau (3 × Tg-AD) mice (10 months old) were randomly divided into four groups: WT+Sham group, WT+OVX group, 3 × Tg-AD+Sham group and 3 × Tg-AD+OVX group. Ovariectomy (OVX) was performed in the WT+OVX group and the 3 × Tg-AD+OVX group, and sham surgery was performed in the WT+Sham group and the 3 × Tg-AD+Sham group. The learning and memory ability and the anxiety and depression-like behavior changes of mice were evaluated by behavioral experiments, and the association between estrogen-estrogen receptors pathway and glutamatergic/GABAergic nervous system and female AD was evaluated by neurochemical experiments. In WT and 3 × Tg-AD mice, OVX resulted in impaired learning and memory abilities and anxiety and depression-like behaviors; reduced estrogen levels and downregulated the expression of estrogen receptors; upregulated the expression of amyloid-β, amyloid precursor protein, presenilin 1, and p-tau; upregulated the expression of Bcl-2-associated X protein and downregulated the expression of B-cell lymphoma-2, promoting cell apoptosis; reduced the number of neuronal dendrites and downregulated the expression of postsynaptic density protein-95; more importantly, OVX increased brain glutamate levels but downregulated the expression of N-methyl-D-aspartate receptor-2B, excitatory amino acid transporter 1, excitatory amino acid transporter 2, γ-aminobutyric acid receptor-A and γ-aminobutyric acid receptor-B. Our results suggested that OVX-induced estrogen-estrogen receptors pathway disruption caused learning and memory impairment and anxiety and depression-like behaviors, upregulated the expression of AD pathological markers, promoted apoptosis, destroyed neuronal structure, and most importantly, caused glutamatergic/GABAergic nervous system disorders.

Secoisolariciresinol diglucoside attenuates neuroinflammation and cognitive impairment in female Alzheimer’s disease mice via modulating gut microbiota metabolism and GPER/CREB/BDNF pathway

BackgroundGender is a significant risk factor for late-onset Alzheimer’s disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear.MethodsTen-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG’s cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG.ResultsSDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced β-amyloid (Aβ) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aβ-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses.ConclusionThese findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral β-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.

An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer's disease

BackgroundAge represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. MethodsThe exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. ResultsWe selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). ConclusionOur meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.

Activation of the hypoxia response in the aging cerebrovasculature protects males against cognitive impairment.

Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.

Anxiety in Alzheimer's disease rats is independent of memory and impacted by genotype, age, sex, and exercise.

Alzheimer's disease (AD) is characterized by cognitive impairments; however, heightened anxiety often accompanies and, in some cases, exacerbates cognitive its. The present study aims to understand the influence of multiple variables on anxiety-like behavior in TgF344-AD rats and determine whether anxiety impacts memory performance. An elevated plus maze was used to assess anxiety-like behavior in the established colony (n=107). Influences of age, sex, genotype, and exercise on anxiety were evaluated via multiple linear regression. Correlation analysis evaluated the relationship between anxiety and memory performance. Age (P<0.05) and AD genotype (P<0.001) were associated with increasing anxiety, while exercise (P<0.05) was associated with decreasing anxiety. Female AD animals displayed more anxiety-like behavior versus wild-type female (P<0.001) and AD male (P<0.05) littermates. Concluding that while factors such as age, sex, AD genotype, and training status can impact anxiety levels in the TgF344-AD model, anxiety level did not impact memory performance. Increased anxiety-like behavior in TgF344-AD rats does not correlate with declines in memory performance. Predictors of higher anxiety-like behaviors in the TgF344-AD rat include age, Alzheimer's disease (AD) genotype, and sex with female AD animals experiencing greater anxiety compared to female wild-type or male AD. Exercise training leads to decreased anxiety-like behaviors in the TgF344-AD rat.

Sex differences in luteinizing hormone aggravates Aβ deposition in APP/PS1 and Aβ1-42-induced mouse models of Alzheimer's disease

Alzheimer's disease (AD) exhibits a higher incidence rate among older women, and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis during aging is associated with cognitive impairments and the development of dementia. luteinizing hormone (LH) has an important role in CNS function, such as mediating neuronal pregnenolone production, and modulating neuronal plasticity and cognition. The sex differences in LH and its impact on Aβ deposition in AD individuals remain unclear, with no reported specific mechanisms. Here, we show through data mining that LH-related pathways are significantly enriched in female AD patients. Additionally, LH levels are elevated in female AD patients and exhibit a negative correlation with cognitive levels but a positive correlation with AD pathology levels, and females exhibit a greater extent of AD pathology, such as Aβ deposition. In vivo, we observed that the exogenous injection of LH exacerbated behavioral impairments induced by Aβ1-42 in mice. LH injection resulted in worsened neuronal damage and increased Aβ deposition. In SH-SY5Y cells, co-administration of LH with Aβ further exacerbated Aβ-induced neuronal damage. Furthermore, LH can dose-dependently decrease the levels of NEP and LHR proteins while increasing the expression of GFAP and IBA1 in vivo and in vitro. Taken together, these results indicate that LH can exacerbate cognitive impairment and neuronal damage in mice by increasing Aβ deposition. The potential mechanism may involve the reduction of NEP and LHR expression, along with the exacerbation of Aβ-induced inflammation.

Leveraging electronic health records and knowledge networks for Alzheimer’s disease prediction and sex-specific biological insights

Identification of Alzheimer’s disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

Plasma Biomarkers in Neurodegenerative Dementias: Unrevealing the Potential of Serum Oxytocin, BDNF, NPTX1, TREM2, TNF-alpha, IL-1 and Prolactin.

Dementia encompasses a range of neurodegenerative disorders characterized by cognitive decline and functional impairment. The identification of reliable biomarkers is essential for accurate diagnosis and gaining insights into the mechanisms underlying diseases. This study aimed to investigate the plasma biomarker profiles associated with Brain- Derived Neurotrophic Factor (BDNF), Oxytocin, Neuronal Pentraxin-1 (NPTX1), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin- 1 (IL-1) and Prolactin in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementias (FTD) and healthy controls. Serum levels of the aforementioned biomarkers were analyzed in 23 AD, 28 DLB, 15 FTD patients recruited from outpatient units and 22 healthy controls. Diagnostic evaluations followed established criteria and standardized clinical tests were conducted. Blood samples were collected and analyzed using ELISA and electrochemiluminescence immunoassay methods. Serum BDNF and oxytocin levels did not significantly differ across groups. NPTX1, TREM2, TNF-alpha and IL-1 levels also did not show significant differences among dementia groups. However, prolactin levels exhibited distinct patterns, with lower levels in male DLB patients and higher levels in female AD patients compared to controls. The study findings suggest potential shared mechanisms in dementia pathophysiology and highlight the importance of exploring neuroendocrine responses, particularly in AD and DLB. However, further research is warranted to elucidate the role of these biomarkers in dementia diagnosis and disease progression.

The role of microRNAs in understanding sex-based differences in Alzheimer’s disease

BackgroundThe incidence of Alzheimer's disease (AD)—the most frequent cause of dementia—is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment.MethodsA systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms.ResultsMeta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process.ConclusionsSex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.

A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer’s disease

Toxic amyloid-beta (Aβ) plaque and harmful inflammation are two leading symptoms of Alzheimer’s disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aβ fibrils formation, degrades Aβ fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.

Female-sensitive multifunctional phytoestrogen nanotherapeutics for tailored management of postmenopausal Alzheimer's disease

Alzheimer's disease (AD) has much higher incidence and mortality in women, largely attributed to the dramatic decline in estrogen levels during menopause. Therefore, tailoring therapeutic strategies targeting estrogen deprivation is essential to achieve female-specific AD treatment. Herein, we developed a multifunctional phytoestrogen nanomodulator (LQ-LPs) and revealed its feasibility and key pharmacological mechanisms for female-sensitive AD management. Benefiting from the greatly improved bioavailability and pharmacokinetics by liposomes, LQ-LPs amplified multiple biological properties of loaded liquiritigenin against estrogen-deprived AD progression, including enhancing synaptoprotective and anti-apoptotic effects through activation of ERβ/BDNF/ERK signaling, as well as simultaneously inhibiting Ca2+ influx spike, oxidative damage, and cholinergic dysfunction caused by glutamate excitotoxicity. Taking advantage of the favorable brain-targeting properties conferred by intranasal delivery, LQ-LP administration exhibited remarkable anti-AD efficacy in reversing ovariectomy-induced neuropathology and rescuing cognitive deficits in estrogen-deprived AD mice. This work reveals for the first time the attractive promise of phytoestrogen-derived versatile nanotherapeutics for female-specific AD management, providing advanced insights into precision drug development for female AD.

Effect of photobiological modulation therapy on cognitive impairment and cardiovascular structure in an APP/PS1 mouse model of Alzheimer’s Disease

AbstractBackgroundPhotobiological modulation (PBM) therapy, a form of low‐dose light therapy, is beneficial in treating various disease conditions including Alzheimer’s disease (AD). Double‐transgenic mice (APPswe/PS1dE9) develop progressive accumulation of amyloid‐β (Aβ) plaques, cognitive impairment, and alterations in cardiovascular structure and function, and represent a model of AD. Prior studies have shown that PBM therapy reduces the size and number of Aβ plaques in the neocortex and hippocampus in the mouse models of AD. The aim of this study was to investigate the effects of PBM on cardiovascular structure and function and cognitive function in the aged AD mice.MethodsSix‐month old female AD (APPswe/PS1dE9; AD‐PBM, n = 8) and wild type mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 6; WT‐CNT, n = 6) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Cardiac parameters were measured by echocardiography. Gait analysis (DigiGait), home cage activity (HCA), and spatial working memory (indicated by alternation rate in cross maze test, CM) were assessed after 6 months of treatment. Group differences were identified by two‐way ANOVA.ResultsIn HCA test, the AD‐CNT mice exhibited circadian locomotor hyperactivity at night‐time relative to WT‐CNT mice (Figure 1A, B), which was reduced by PBM. AD‐CNT mice had lower alternation rates in CM, indicating spatial working memory impairment. PBM had minimal effect on this parameter (Table 1). The AD‐CNT vs. WT‐CNT mice manifested differences in several gait parameters, specifically, they demonstrated a lower fore propel time than WT‐CNT. PBM normalized this parameter in AD‐PBM mice to the level of WT‐CNT (Figure 1C). Both WT‐PBM and AD‐PBM mice had improved cardiovascular structure, which was demonstrated by lower relative wall thickness of left ventricle (LV) and LV mass, and higher LV volume at the end of diastole in PBM‐treated vs. correspondent CNT groups (Table 1, Figure 2).ConclusionPBM improved cardiovascular structure and AD‐associated cognitive impairment in the APP/PS1 mouse model. It is possible that more effective cardiovascular structure and function contributes to Aβ removal from the brain after PBM treatment. Supported by NIA/NIH/IRP

Sex‐specific neuropsychiatric burden distinguished by APOE4 status and cortical thickness

AbstractBackgroundThe APOE ε4 (APOE4) allele is a genetic risk factor for Alzheimer’s disease (AD). Prior work by our group found a significant association between the APOE4 allele and presence of psychosis as well as overall increased neuropsychiatric symptom (NPS) burden in female APOE4 homozygote AD patients, with no effect present in males. In this study, we sought to examine the relationship between APOE4 carrier status and sex on NPS burden from a neuroimaging perspective, with the aim to determine what brain regions may be driving this effect.MethodA cohort of 752 AD patients were selected from the National Alzheimer’s Coordinating Center (NACC) database: 104 APOE4 homozygotes (40F|64M), 304 APOE4 heterozygotes (160F|144M) and 310 APOE4 non‐carriers (131F|179M). Presence of NPS was identified using the Neuropsychiatric Inventory (NPI). Structural T1‐weighted images were downloaded from the NACC imaging dataset and cortical thickness measures corresponding to frontal, cingulate, temporal and parietal regions were assessed. Statistical analysis included a Bayesian multilevel regression where cortical thickness was modeled as an outcome variable against an interaction between sex and APOE4 homozygote status (0|1), while controlling for heterozygote status, APOE4 non‐carrier status, age, sex and MMSE as predictor variables. Within‐ and between‐groups mean differences in thickness were measured as a probability density estimate (Highest Density interval), and partial correlation was used to examine NPI correlates to thickness.ResultFemale APOE4 homozygotes displayed a high probability (&gt;90%HDI) of greater cortical thickness in the posterior cingulate and isthmus cingulate regions bilaterally and reduced cortical thickness in temporal regions (Figure 1). Cortical thickness in the fusiform cortex was positively correlated to greater NPI burden (p&lt;0.05) among female homozygotes, and negatively correlated to NPI burden among female heterozygotes. Cortical thickness in males, regardless of carrier status, did not correlate to NPI burden in any region.ConclusionThis study highlights an important relationship between the fusiform cortex and NPI burden in female APOE4 carriers, marking a female‐specific effect. Future work should further disentangle sex differences in APOE4 status and psychosis with a focus on the fusiform cortex as a potential region of interest.

Sex and age dependent effects of gut microbiota manipulation in AppSAA mouse model of Alzheimer disease

AbstractBackgroundPopulation based studies indicate that women are at significantly greater risk of developing Alzheimer’s disease (AD) than men. Gut microbiome is involved in the pathogenesis of AD however sex specific (/differential) effect of gut microbiome manipulation is not well understood.MethodTo determine the effect of sex and age on the impact of gut microbiota manipulation on cognitive outcomes, 3‐4 months old male and females AppSAA mice (AD) were treated with probiotics (for 8 weeks) and antibiotics for (10‐days) along with C57BL/6J and hApp as controls. Based on our previous studies, probiotic had beneficial effects on younger AD females and had no effect on males. To understand if gut bacteria are directly involved in eliciting these differential effects, we collected the stool samples from AD females treated with probiotic (VSL#3) and did fecal microbiota transplantation (FMT) in younger and older male and female AD mice. Neurobehavioral testing was performed including Open field task (OFT), Y‐Maze, Contextual fear conditioning (CFC) and Novel object recognition. Brain and intestine samples were collected for biochemical and molecular characterization.ResultIn OFT, AppSAA mice travelled more distance as compared to C57BL/6J, and treating AppSAA mice with probiotic or antibiotic resulted in increased distance traveled. Antibiotic mice also showed less freezing in CFC task when compared to controls. Overall, FMT mice had a trend towards lower mean speed and distance travelled on Y‐maze with no significant change in memory functions. That said, the AppSAA mice at 5‐6 months of age showed no significant memory deficits as assessed using CFC and Y‐maze, and will need to be aged further to assess the effect of antibiotics and FMT on cognitive deficits.ConclusionTreating AppSAA mice with probiotic or FMT (samples from probiotic treated females to AD young and old animals) had effects on motor behavior, but no effects in terms of memory functions. This lack of change is not surprising, as AD mice at early age did not demonstrate a behavioral phenotype compared to controls. Currently, we are doing biochemical analysis to elucidate if FMT influenced brain pathology (inflammation or Aβ) in AD mice.