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Cryptorchidism is a congenital abnormality resulting in increased rates of infertility and testicular cancer. We used cryptorchidism model mice that presented with the translocation of the left testis from the scrotum to the abdominal cavity. Mice underwent the surgical procedure of the left testis at day 0 and were sacrificed at days 3, 5, 7, 14, 21, and 28 post-operatively. The weight of the left cryptorchid testis decreased significantly at days 21 and 28. The morphological changes were observed after 5 days and showed detached spermatogenic cells and abnormal formation of acrosome at day 5, multinucleated giant cells at day 7, and atrophy of seminiferous tubules at days 21 and 28. The high abdominal temperature disrupted the normal expression of cell adhesion molecule-1, Nectin-2, and Nectin-3 which are essential for spermatogenesis. In addition, the pattern and alignment of acetylated tubulin in cryptorchid testes were also changed at days 5, 7, 14, 21, and 28. Ultrastructure of cryptorchid testes revealed giant cells that had been formed by spermatogonia, spermatocytes, and round and elongating spermatids. The study's findings reveal that cryptorchidism's duration is linked to abnormal changes in the testis, impacting protein marker expression in spermatogenic and Sertoli cells. These changes stem from the induction of high abdominal temperature. [ABSTRACT FROM AUTHOR]

Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes. [ABSTRACT FROM AUTHOR]

Pesticides have a number of significant benefits to humans with improved crop yield and controlled vector populations. The pesticides such as organochlorines, organophosphates and carbamates cause toxicity by either targeting the nervous system of the prospective pests or by generating reactive oxygen species (ROS). Because humans are also exposed to them in the runaway process, there is an increasing risk of toxicity such as neurotoxicity or carcinogenicity. Apart from altering signal transduction pathways, disruption of protein phosphorylating pathways, hormonal impairment, etc., the pesticides interact with proteins, which may lead to various unexplored physiological consequences. Focusing on pesticides induced neurotoxicity, the interaction of pesticides with human serum albumin (HSA) and anti-proteinase alpha-2-macroglobulin (α2M) has been discussed in the review article. The article presents a possible unexplored mechanism of neurotoxicity of pesticides and their interaction with α2M, as it has a defensive role in the clearance of beta amyloid plaques in brain. This review also focuses on the possibilities of pesticide interaction with other non-plasma proteins leading to unknown biological consequences yet to be investigated. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases represent a large group of disorders characterized by gradual loss of neurons and functions of the central nervous systems. Their course is usually severe, leading to high morbidity and subsequent inability of patients to independent functioning. Vast majority of neurodegenerative diseases is currently untreatable, and only some symptomatic drugs are available which efficacy is usually very limited. To develop novel therapies for this group of diseases, it is crucial to understand their pathogenesis and to recognize factors which can influence the disease course. One of cellular structures which dysfunction appears to be relatively poorly understood in the light of neurodegenerative diseases is tubulin cytoskeleton. On the other hand, its changes, both structural and functional, can considerably influence cell physiology, leading to pathological processes occurring also in neurons. In this review, we summarize and discuss dysfunctions of tubulin cytoskeleton in various neurodegenerative diseases different than primary tubulinopathies (caused by mutations in genes encoding the components of the tubulin cytoskeleton), especially Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, and neuronopathic mucopolysaccharidoses. It is also proposed that correction of these disorders might attenuate the progress of specific diseases, thus, finding newly recognized molecular targets for potential drugs might become possible. [ABSTRACT FROM AUTHOR]

In Ehrlich ascites tumor cells maintained in serum-free medium for 16 h the rate of protein synthesis was about 50% of the rate in control (well-fed) cells. The addition of 10% calf serum led to a 1.5- to 2-fold stimulation of protein synthesis within 10 min. Stimulation was effected through a non-transcriptional mechanism which operated at the level of polypeptide chain initiation. The effect was due to non-dialyzable serum growth factors which were sensitive to treatment with dithiothreitol and iodoacetamide. Replacing the 16-h-conditioned serum-free medium with fresh serum-free medium stimulated protein synthesis about 30% in serum-deprived cells, and the effect of these low molecular weight nutrients was additive with the effect of serum factors. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) inhibits protein synthesis by competitively inhibiting the guanine nucleotide exchange factor (GEF), and modulation of the extent of phosphorylation of eIF-2 alpha has been suggested as a probable regulatory mechanism in serum-deprived mammalian cells. We measured the ratio of phosphorylated to total eIF-2 alpha in serum-deprived cells. The ratio was elevated in serum-deprived cells compared to control (serum-fed) cells. eIF-2 was rapidly dephosphorylated in response to serum refeeding and returned to near control levels after 10 min. The rapidity of this response and the close temporal correlation between eIF-2 dephosphorylation and increased rate of protein synthesis provide evidence that eIF-2 plays an important role in the regulation of protein synthesis by serum growth factors.

Previously, we have shown that phosphorylation of the eukaryotic initiation factor eIF-2 alpha increases under several physiological stresses in which protein synthesis is inhibited in Ehrlich ascites tumor cells. As phosphorylated eIF-2 [eIF-2(alpha P)] is a potent inhibitor of guanine nucleotide exchange factor (GEF), it seemed likely that it was responsible for the inhibition. We have assayed GEF activity levels in extracts prepared from Ehrlich cells exposed to three such stresses, namely heat shock, serum deprivation and glutamine deprivation. Activity was estimated by the ability of GEF to enhance the release of [alpha-32P]GDP from purified eIF-2 [a modification of the reticulocyte lysate assay of Matts, R. L. & London, I. M. (1984) J. Biol. Chem. 259, 6708]. GEF activity was reduced from control values in extracts of heat-shocked cells and serum-deprived cells, concomitant with increased eIF-2 alpha phosphorylation. Inhibition of GEF activity in heat-shocked and serum-deprived cells was reversed to control levels by increasing the concentration of purified eIF-2.GDP added as substrate in the GEF assay. Since we have shown elsewhere that eIF-2(alpha P).GDP inhibits GEF by competition with eIF-2.GDP, the complete reversal of inhibition of GEF activity in heat-shocked and serum-deprived cells indicates that inhibition is due solely to phosphorylation of eIF-2 alpha. In glutamine-deprived cells phosphorylation of eIF-2 alpha was increased modestly and GEF activity was reduced but GEF activity could not be fully reversed by addition of eIF-2.GDP, suggesting that GEF may also be regulated in other ways. There are greater amounts of GEF relative to eIF-2 in Ehrlich cells (approximately 50%) compared with rabbit reticulocytes (approximately 20%). This explains the efficient rates of protein synthesis in control Ehrlich cells even though they have 30% of their eIF-2 phosphorylated which is enough to inhibit GEF and initiation in reticulocytes completely but only enough to trap approximately 60% of the GEF in Ehrlich cells.

Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathy (CAA). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that approximately correlated with gold-standard human CERAD-like WSI scoring (p = 0.07 ± 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation. A deep learning model rapidly identifies locality and counts of cored plaques and cerebral amyloid angiopathy in whole slide images comparably to human experts and without a GPU on a standard workstation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive degenerative disease of the nervous system (CNS) with an insidious onset. Clinically, it is characterized by a full range of dementia manifestations including memory impairment, aphasia, loss of speech, loss of use, loss of recognition, impairment of visuospatial skills, and impairment of executive function, as well as changes in personality and behavior. The exact cause of AD has not yet been identified. Nevertheless, modern research indicates that genetic factors contribute to 70% of human's risk of AD. Apolipoprotein (APOE) accounts for up to 90% of the genetic predisposition. APOE is a crucial gene that cannot be overstated. In addition, innate immunity plays a significant role in the etiology and treatment of AD. Understanding the different subtypes of APOE and their interconnections is of paramount importance. APOE and innate immunity, along with their relationship to AD, are primary research motivators for in-depth research and clinical trials. The exploration of novel technologies has led to an increasing trend in the study of AD at the cellular and molecular levels and continues to make more breakthroughs and progress. As of today, there is no effective treatment available for AD around the world. This paper aims to summarize and analyze the role of APOE and innate immunity, as well as development trends in recent years. It is anticipated that APOE and innate immunity will provide a breakthrough for humans to hinder AD progression in the near future. [ABSTRACT FROM AUTHOR]

Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission. [ABSTRACT FROM AUTHOR]

Background: Considering the strong correlation made between Alzheimer's disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD.Objective: Reveal the pathological relationship between AD and insulin resistance.Methods: We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE).Results: 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p < 0.001), FINS (p < 0.001), and HOMA-IR (p < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p = 0.001) and positively related to the sex ratio (male versus female) (p < 0.05). HOMA-IR obeyed lognormal distribution (p > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p = 0.479) was positively correlated to MMSE, while FINS (p = 0.1657) was negatively correlated with MMSE.Conclusion: The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients. [ABSTRACT FROM AUTHOR]

Maintenance of calcium homeostasis is important for proper endoplasmic reticulum (ER) function. When cellular stress conditions deplete the high concentration of calcium in the ER, ER-resident proteins are secreted into the extracellular space in a process called exodosis. Monitoring exodosis provides insight into changes in ER homeostasis and proteostasis resulting from cellular stress associated with ER calcium dysregulation. To monitor cell-type specific exodosis in the intact animal, we created a transgenic mouse line with a Gaussia luciferase (GLuc)—based, secreted ER calcium-modulated protein, SERCaMP, preceded by a LoxP-STOP-LoxP (LSL) sequence. The Cre-dependent LSL-SERCaMP mice were crossed with albumin (Alb)-Cre and dopamine transporter (DAT)-Cre mouse lines. GLuc-SERCaMP expression was characterized in mouse organs and extracellular fluids, and the secretion of GLuc-SERCaMP in response to cellular stress was monitored following pharmacological depletion of ER calcium. In LSL-SERCaMP × Alb-Cre mice, robust GLuc activity was observed only in the liver and blood, whereas in LSL-SERCaMP × DAT-Cre mice, GLuc activity was seen in midbrain dopaminergic neurons and tissue samples innervated by dopaminergic projections. After calcium depletion, we saw increased GLuc signal in the plasma and cerebrospinal fluid collected from the Alb-Cre and DAT-Cre crosses, respectively. This mouse model can be used to investigate the secretion of ER-resident proteins from specific cell and tissue types during disease pathogenesis and may aid in the identification of therapeutics and biomarkers of disease. [ABSTRACT FROM AUTHOR]

High levels of 4‐hydroxynonenal (HNE), arising from lipid peroxidation, and HNE‐modified proteins have been identified in postmortem brains of ageing and Alzheimer's disease (AD) patients. The goal of this study is to understand the effect of HNE modification on the structure and function of recombinant apolipoprotein E3 (apoE3) and apolipoprotein E4 (apoE4), which play a critical role in brain cholesterol homeostasis. The two isoforms differ in a single amino acid at position 112: Cys in apoE3 and Arg in apoE4. Immunoblot with HNE‐specific antibody indicates HNE modification of apoE3 and apoE4 with a major band at ~ 36 kDa, while LC–MS/MS revealed Michael addition at His140 (60–70% abundance) and His299 (3–5% abundance) in apoE3 and apoE4, and Cys112 adduct in apoE3 (75% abundance). Circular dichroism spectroscopy revealed no major differences in the overall secondary structure or helical content between unmodified and HNE‐modified apoE. HNE modification did not affect their ability to promote cholesterol efflux from J774.1 macrophages. However, it led to a 3‐fold decrease in their ability to bind lipids and 25–50% decrease in the ability of cerebral cortex endothelial cells to uptake lipoproteins bearing HNE‐modified HNE‐apoE3 or HNE‐apoE4 as noted by fluorescence microscopy and flow cytometry. Taken together, the data indicate that HNE modification impairs lipid binding and cellular uptake of both isoforms, and that apoE3, bearing a Cys, offers a protective role by sequestering lipid peroxidation products that would otherwise cause indiscriminate damage to biomolecules. ApoE4, lacking Cys, is unable to protect against oxidative damage that is commensurate with ageing. [ABSTRACT FROM AUTHOR]

The worldwide prevalence of Parkinson's disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come. [ABSTRACT FROM AUTHOR]

With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience. [ABSTRACT FROM AUTHOR]

The COVID-19 global pandemic has underscored the need to understand how viruses and other pathogens are able to infect and replicate within the respiratory system. Recent studies have highlighted the role of highly O-glycosylated mucins in the protection of the respiratory system as well as how mucin-type O-glycosylation may be able to modify viral infectivity. Therefore, we set out to identify the specific genes controlling mucin-type O-glycosylation throughout the mouse respiratory system as well as determine how their expression and the expression of respiratory mucins is influenced by infection or injury. Here, we show that certain mucins and members of the Galnt family are abundantly expressed in specific respiratory tissues/cells and demonstrate unique patterns of O-glycosylation across diverse respiratory tissues. Moreover, we find that the expression of certain Galnts and mucins is altered during lung infection and injury in experimental mice challenged with infectious agents, toxins, and allergens. Finally, we examine gene expression changes of Galnt s and mucins in a mouse model of SARS-CoV-2 infection. Our work provides foundational knowledge regarding the specific expression of Galnt enzyme family members and mucins throughout the respiratory system, and how their expression is altered upon lung infection and injury. [ABSTRACT FROM AUTHOR]

Background: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers. Objective: Our objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals. Methods: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education. Results: Alzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48–47.44) and neocortical (OR = 10.80;95% CI: 1.03–113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10–25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP. Conclusion: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing. Methods: Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD. Results: Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons. Conclusions: Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD. [ABSTRACT FROM AUTHOR]

Background: Cognitive status classification (e.g. dementia, cognitive impairment without dementia, and normal) based on cognitive performance questionnaires has been widely used in population-based studies, providing insight into the population dynamics of dementia. However, researchers have raised concerns about the accuracy of cognitive assessments. MRI and CSF biomarkers may provide improved classification, but the potential improvement in classification in population-based studies is relatively unknown. Methods: Data come from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined whether the addition of MRI and CSF biomarkers improved cognitive status classification based on cognitive status questionnaires (MMSE). We estimated several multinomial logistic regression models with different combinations of MMSE and CSF/MRI biomarkers. Based on these models, we also predicted prevalence of each cognitive status category using a model with MMSE only and a model with MMSE + MRI + CSF measures and compared them to diagnosed prevalence. Results: Our analysis showed a slight improvement in variance explained (pseudo-R2) between the model with MMSE only and the model including MMSE and MRI/CSF biomarkers; the pseudo-R2 increased from.401 to.445. Additionally, in evaluating differences in predicted prevalence for each cognitive status, we found a small improvement in the predicted prevalence of cognitively normal individuals between the MMSE only model and the model with MMSE and CSF/MRI biomarkers (3.1% improvement). We found no improvement in the correct prediction of dementia prevalence. Conclusion: MRI and CSF biomarkers, while important for understanding dementia pathology in clinical research, were not found to substantially improve cognitive status classification based on cognitive status performance, which may limit adoption in population-based surveys due to costs, training, and invasiveness associated with their collection. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the primary chemicals produced by volume worldwide. Extensive literature has raised many concerns about its possible involvement in the pathogenesis of kidney diseases, but its contribution has not been extensively studied. During cellular senescence, the interference of lipofuscin with cellular functions promotes further senescence, causing cellular malfunction. Insulin-like growth factor-1 (IGF-1) plays an important protective role in the setting of kidney injury. The goal of the present work was to evaluate the effects of short-term treatment with low doses of BPA on cellular senescence in adult rat kidneys. Male Wistar rats were injected with vehicle (CONTROL group) or 50 or 500 μg/kg/day of BPA for 1 week (BPA50 and BPA500 groups, respectively). The kidneys were fixed in 4% buffered formaldehyde and embedded in paraffin. Immunohistochemical analyses were performed, and an immunoreactive score (IRS) was calculated. Lipofuscin autofluorescence was used for the study of cellular senescence. The renal cortex showed diffuse autofluorescent lipofuscin signal in the proximal convoluted tubules (PCTs) of males in the BPA50-treated (weak intensity) and BPA500-treated (strong intensity) groups, but not in CONTROL males. Labeling of cortical PCTs with anti-IGF-1 antibodies showed an IRS of 0 in the CONTROL group, but IRSs of 4 and 6 in the BPA50- and BPA500-treated groups, respectively. The present results suggest that low, "safe" doses of BPA induce renal injury, as measured by histological signs of renal changes, increased cellular senescence, and activation of cellular repair systems in PCTs. [ABSTRACT FROM AUTHOR]

Background: An increasing number of experimental and clinical studies show a link between Alzheimer's disease and heart diseases such as heart failure, ischemic heart disease, and atrial fibrillation. However, the mechanisms underlying the potential role of amyloid-β (Aβ) in the pathogenesis of cardiac dysfunction in Alzheimer's disease remain unknown. We have recently shown the effects of Aβ1 - 40 and Aβ1 - 42 on cell viability and mitochondrial function in cardiomyocytes and coronary artery endothelial cells. Objective: In this study, we investigated the effects of Aβ1 - 40 and Aβ1 - 42 on the metabolism of cardiomyocytes and coronary artery endothelial cells. Methods: Gas chromatography-mass spectrometry was used to analyze metabolomic profiles of cardiomyocytes and coronary artery endothelial cells treated with Aβ1 - 40 and Aβ1 - 42. In addition, we determined mitochondrial respiration and lipid peroxidation in these cells. Results: We found that the metabolism of different amino acids was affected by Aβ1 - 42 in each cell type, whereas the fatty acid metabolism is consistently disrupted in both types of cells. Lipid peroxidation was significantly increased, whereas mitochondrial respiration was reduced in both cell types in response to Aβ1 - 42. Conclusion: This study revealed the disruptive effects of Aβ on lipid metabolism and mitochondria function in cardiac cells. [ABSTRACT FROM AUTHOR]

Unlike immature neurons and the ones from the peripheral nervous system (PNS), mature neurons from the central nervous system (CNS) cannot regenerate after injury. In the past 15 years, tremendous progress has been made to identify molecules and pathways necessary for neuroprotection and/or axon regeneration after CNS injury. In most regenerative models, phosphorylated ribosomal protein S6 (p-RPS6) is up-regulated in neurons, which is often associated with an activation of the mTOR (mammalian target of rapamycin) pathway. However, the exact contribution of posttranslational modifications of this ribosomal protein in CNS regeneration remains elusive. In this study, we demonstrate that RPS6 phosphorylation is essential for PNS and CNS regeneration in mice. We show that this phosphorylation is induced during the preconditioning effect in dorsal root ganglion (DRG) neurons and that it is controlled by the p90S6 kinase RSK2. Our results reveal that RSK2 controls the preconditioning effect and that the RSK2-RPS6 axis is key for this process, as well as for PNS regeneration. Finally, we demonstrate that RSK2 promotes CNS regeneration in the dorsal column, spinal cord synaptic plasticity, and target innervation leading to functional recovery. Our data establish the critical role of RPS6 phosphorylation controlled by RSK2 in CNS regeneration and give new insights into the mechanisms related to axon growth and circuit formation after traumatic lesion. This study shows that RSK2-controlled phosphorylation of RPS6 on Ser233/236 is critical for peripheral and central nervous system regeneration and functional recovery through modulation of spinal cord plasticity and target innervation. [ABSTRACT FROM AUTHOR]

Aberrant splicing is typically attributed to splice‐factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation‐independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice‐factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice‐site selection for ~800 transcripts in cell lines and ~4,600 transcripts in specimens from high‐eIF4E AML patients otherwise harboring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses, and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. By contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre‐mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in the case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation. Synopsis: Aberrant splicing in diseases such as AML is typically attributed to splice‐factor (SF) mutation or dysregulation of specific splicing factors. Here, eukaryotic translation initiation factor eIF4E is reported to induce broad‐range alternative splicing by simultaneously affecting multiple splicing factors.eIF4E induces the production of several SFs simultaneously by promoting nuclear mRNA export and directly interacting with a subset of pre‐mRNAs.A separation‐of‐function mutant of eIF4E shows that the loss of nuclear export activity severely impairs SF production.eIF4E physically associates with several components of the major spliceosome complexes.eIF4E interaction with RNAs is predominantly mediated by the m7G cap.eIF4E overexpression does not lead to global transcriptomic changes but alters splice‐site selection for thousands of transcripts in cell lines and AML patient specimens.eIF4E‐dependent splicing is dysregulated in primary high‐eIF4E AML patient samples. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an advanced neurodegenerative disease (NDD) caused by the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). As PD is an age-related disorder, the majority of PD patients are associated with musculoskeletal disorders with prolonged use of analgesic and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, NSAIDs can affect PD neuropathology in different ways. Thus, the objective of the present narrative review was to clarify the potential role of NSAIDs in PD according to the assorted view of preponderance. Inhibition of neuroinflammation and modulation of immune response by NSAIDs could be an effective way in preventing the development of NDD. NSAIDs affect PD neuropathology in different manners could be beneficial or detrimental effects. Inhibition of cyclooxygenase 2 (COX2) by NSAIDs may prevent the development of PD. NSAIDs afforded a neuroprotective role against the development and progression of PD neuropathology through the modulation of neuroinflammation. Though, NSAIDs may lead to neutral or harmful effects by inhibiting neuroprotective prostacyclin (PGI2) and accentuation of pro-inflammatory leukotrienes (LTs). In conclusion, there is still a potential conflict regarding the effect of NSAIDs on PD neuropathology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia, affecting millions of people worldwide. Oxidative stress contributes towards induction of neurodegeneration. It is one of the reasons behind initiation and progression of Alzheimer's disease. Understanding of oxidative balance and restoration of oxidative stress has demonstrated its effectiveness in the management of AD. Various natural and synthetic molecules have been found to be effective in different models of AD. Some clinical studies also support the use of antioxidants for prevention of neurodegeneration in AD. In this review we are summarizing the development of antioxidants to restrict oxidative stress induced neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I–IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset. Results: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC. [ABSTRACT FROM AUTHOR]

Purpose: Sex differences in Alzheimer's disease (AD) progression provide clues to pathogenesis and better patient management. We examined sex differences in emotional memory among AD patients, amnestic mild cognitive impairment (aMCI) patients, and healthy controls (HCs) as well as potential associations with altered regional cerebral blood flow (rCBF). Methods: The recognition memory task with emotional pictures was applied to evaluate enhancement of emotional memory (EEM) and 3D pseudo-continuous arterial spin labeling MRI was performed to measure the rCBF in 74 AD patients (41 females), 74 aMCI patients (45 females), and 74 HCs (43 females). Group differences in EEM were tested by two-way analysis of covariance (ANCOVA) with repeated measures. The main effects of clinical group and sex as well as group × sex interactions on rCBF were assessed by two-way ANCOVA. Correlation analyses were conducted to investigate associations between EEM and rCBF. Results: With disease progression, EEM gradually disappeared. Among aMCI patients, females exhibited a greater index of recollection (Pr) for positive/high-arousal and negative/low-arousal pictures versus neutral pictures (P = 0.005, P = 0.003), while males exhibited a greater Pr for negative/high-arousal versus neutral pictures (P = 0.001). There were significant sex × group effects on rCBF in left inferior parietal, supramarginal, superior temporal and middle temporal gyri, and rCBF of left inferior parietal gyrus was correlated with Pr for positive/high-arousal pictures among female aMCI patients (r = 0.584, q = 0.005). Conclusion: Males and females exhibit distinct changes in EEM associated with altered rCBF, which should be considered in future neuroimaging studies. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD), the most common form of dementia globally, classically defined a clinicopathological entity, is a heterogenous disorder with various pathobiological subtypes, currently referred to as Alzheimer continuum. Its morphological hallmarks are extracellular parenchymal β-amyloid (amyloid plaques) and intraneuronal (tau aggregates forming neurofibrillary tangles) lesions accompanied by synaptic loss and vascular amyloid deposits, that are essential for the pathological diagnosis of AD. In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been described that show distinct clinical features, differences in age, sex distribution, biomarker levels, and patterns of key network destructions responsible for cognitive decline. AD is a mixed proteinopathy (amyloid and tau), frequently associated with other age-related co-pathologies, such as cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease. These and other co-pathologies essentially influence the clinical picture of AD and may accelerate disease progression. The purpose of this review is to provide a critical overview of AD pathology, its defining pathological substrates, and the heterogeneity among the Alzheimer spectrum entities that may provide a broader diagnostic coverage of this devastating disorder as a basis for implementing precision medicine approaches and for ultimate development of successful disease-modifying drugs for AD.

Neurodevelopmental disorders are a group of diseases with cognitive, motor, and emotional development deficits. Alpha-synuclein (α-syn) is a synaptic protein involved in transmission and neurodevelopment. This protein was previously shown to be associated with several disorders, including Parkinson's disease. Furthermore, a close link between neurodevelopmental disorders and Parkinson's has also been found. Changes in synaptic function have been noticed in neurodevelopmental disorders, including autism spectrum disorder. Impaired neurogenesis and related cognitive problems have been associated with altered expression of α-syn. Various studies reported α-syn in different body fluids and tissues such as blood and serum. Alpha-synuclein can help in better understanding the pathogenesis of neurodevelopmental diseases and facilitating their early diagnosis. This review aims to go over the recent advances in the role of α-syn in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, and motor and social impairment, and its value as a diagnostic biomarker., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Parkinson's disease is a neurological disorder caused by the loss of dopaminergic neurons in the midbrain. Various mechanisms are involved in the incidence of the disease including oxidative stress. Several herbs and natural products may interfere with the oxidative-stress pathway due to their antioxidant effects., Objective: Herein, we aimed to investigate the neuroprotective role of F. vaillantii extract on Parkinson's in vitro and in vivo model owing to the presence of the bioactive agents with antioxidant properties., Methods: In vitro experments showed that 6-hydroxydopamine could induce toxicity in PC12 cells. The impact of F. vaillantii extract on cell viability was measured by using MTT assay. Nuclear morphological changes were qualitatively evaluated employing Hoechst staining. The antioxidant activity of the extract was determined by ROS and lipid peroxidation assays. Tyrosine hydroxylase protein expression was measured by western blotting in PC12 cells. For in vivo study, movement parameters were evaluated., Results: The results indicated that 75 µΜ of 6-OHDA induced 50% toxicity in PC12 cells for 24 h. Following post-treatment with F. vaillantii extract (0.1 mg/ml) for 72 h, we observed that the extract effectively prevented cell toxicity induced by 6-OHDA and reduced the apoptotic cell population. Furthermore, the extract attenuated the ROS level, lipid peroxidation and increased protein expression of TH after 72 h of treatment. In addition, oral administration of 300 mg/kg of F. vaillantii extract for 14 days improved locomotor activity, catalepsy, bradykinesia, motor coordination and reduced the apomorphine-caused rotation in 6-OHDA- induced Parkinson's disease-like symptoms in male rats., Conclusion: The present study suggests a protective role for the extract of F. vaillantii against oxidative stress-induced cell damage in the PC12 cells exposed to neurotoxin 6-OHDA which was verified in in vivo model by reducing the motor defects induced by 6-OHDA. This extract could be a promising therapeutic agent for the prevention of PD progression., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The fallopian tube (FT) plays a crucial role in the reproductive process by providing an ideal biomechanical and biochemical environment for fertilization and early embryo development. Despite its importance, the biomechanical functions of the FT that originate from its morphological aspects, and ultrastructural aspects, as well as the mechanical properties of FT, have not been studied nor used sufficiently, which limits the understanding of fertilization, mechanotrasduction, and mechanobiology during embryo development, as well as the replication of the FT in laboratory settings for infertility treatments. This paper reviews and revives valuable information on human FT reported in medical literature in the past five decades relevant to the biomechanical aspects of FT. In this review, we summarized the current state of knowledge concerning the morphological, ultrastructural aspects, and mechanical properties of the human FT. We also investigate the potential arising from a thorough consideration of the biomechanical functions and exploring often neglected mechanical aspects. Our investigation encompasses both macroscopic measurements (such as length, diameter, and thickness) and microscopic measurements (including the height of epithelial cells, the percentage of ciliated cells, cilia structure, and ciliary beat frequency). Our primary focus has been on healthy women of reproductive age. We have examined various measurement techniques, encompassing conventional metrology, 2D histological data as well as new spatial measurement techniques such as micro-CT., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

SARS-CoV-2 spike proteins have been shown to cross the blood-brain barrier (BBB) in mice and affect the integrity of human BBB cell models. However, the effects of SARS-CoV-2 spike proteins in relation to sporadic, late onset, Alzheimer's disease (AD) risk have not been extensively investigated. Here we characterized the individual and combined effects of SARS-CoV-2 spike protein subunits S1 RBD, S1 and S2 on BBB cell types (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) generated from induced pluripotent stem cells (iPSCs) harboring low (APOE3 carrier) or high (APOE4 carrier) relative Alzheimer's risk. We found that treatment with spike proteins did not alter iBEC integrity, although they induced the expression of several inflammatory cytokines. iAstrocytes exhibited a robust inflammatory response to SARS-CoV-2 spike protein treatment, with differences found in the levels of cytokine secretion between spike protein-treated APOE3 and APOE4 iAstrocytes. Finally, we tested the effects of potentially anti-inflammatory drugs during SARS-CoV-2 spike protein exposure in iAstrocytes, and discovered different responses between spike protein treated APOE4 iAstrocytes and APOE3 iAstrocytes, specifically in relation to IL-6, IL-8 and CCL2 secretion. Overall, our results indicate that APOE3 and APOE4 iAstrocytes respond differently to anti-inflammatory drug treatment during SARS-CoV-2 spike protein exposure with potential implications to therapeutic responses., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy., (© 2024. Controlled Release Society.)

Comparative experimental pathology is a research field at the interface of human and veterinary medicine. It is focused on the comparative study of similarities and differences between spontaneous and experimentally induced diseases in animals (animal models) compared to human diseases. The use of animal models for studying human diseases is an essential component of biomedical research. Interdisciplinary teams with species-specific expertise should collaborate wherever possible and maintain close communication. Mutual openness, cooperation, and willingness to learn form the basis for a fruitful collaboration. Research projects jointly led by or involving both animal and human pathologists make a significant contribution to high-quality biomedical research. Such approaches are promising not only in oncological research, as outlined in this article, but also in other research areas where animal models are regularly used, such as infectiology, neurology, and developmental biology., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

X chromosome inactivation (XCI) in mammals is mediated by Xist RNA which functions in cis to silence genes on a single X chromosome in XX female cells, thereby equalising levels of X-linked gene expression relative to XY males. XCI progresses over a period of several days, with some X-linked genes silencing faster than others. The chromosomal location of a gene is an important determinant of silencing rate, but uncharacterised gene-intrinsic features also mediate resistance or susceptibility to silencing. In this study, we examine mouse embryonic stem cell lines with an inducible Xist allele (iXist-ChrX mESCs) and integrate allele-specific data of gene silencing and decreasing inactive X (Xi) chromatin accessibility over time courses of Xist induction with cellular differentiation. Our analysis reveals that motifs bound by the transcription factor YY1 are associated with persistently accessible regulatory elements, including many promoters and enhancers of slow-silencing genes. We further show that YY1 is evicted relatively slowly from target sites on Xi, and that silencing of X-linked genes is increased upon YY1 degradation. Together our results suggest that YY1 acts as a barrier to Xist-mediated silencing until the late stages of the XCI process., (© 2024. Crown.)

Parkinson's disease (PD) is an aging-associated neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein within these neurons. Oligomeric α-synuclein exerts neurotoxic effects through mitochondrial dysfunction, glial cell inflammatory response, lysosomal dysfunction and so on. α-synuclein aggregation, often accompanied by oxidative stress, is generally considered to be a key factor in PD pathology. At present, emerging evidences suggest that metabolism alteration is closely associated with α-synuclein aggregation and PD progression, and improvement of key molecules in metabolism might be potentially beneficial in PD treatment. In this review, we highlight the tripartite relationship among metabolic changes, α-synuclein aggregation, and oxidative stress in PD, and offer updated insights into the treatments of PD, aiming to deepen our understanding of PD pathogenesis and explore new therapeutic strategies for the disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neurotoxicity associated with chemotherapy is a debilitating side effect of cancer management in humans which reportedly involves inflammatory and oxidative stress responses. Diphenyl diselenide (DPDS) is an organoselenium compound which exhibits its anti-tumoral, anti-oxidant, anti-inflammatory and anti-mutagenic effects. Nevertheless, its possible effect on chemotherapy-induced neurotoxicity is not known. Using rat model, we probed the behavioral and biochemical effects accompanying administration of antineoplastic agent doxorubicin (7.5 mg/kg) and DPDS (5 and 10 mg/kg). Anxiogenic-like behavior, motor and locomotor insufficiencies associated with doxorubicin were considerably abated by both DPDS doses with concomitant enhancement in exploratory behavior as demonstrated by reduced heat maps intensity and enhanced track plot densities. Moreover, with exception of cerebral glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, biochemical data demonstrated reversal of doxorubicin-mediated decline in cerebral and cerebellar antioxidant status indices and the increase in acetylcholinesterase (AChE) activity by both doses of DPDS. Also, cerebellar and cerebral lipid peroxidation, hydrogen peroxide as well as reactive oxygen and nitrogen species levels were considerably diminished in rats administered doxorubicin and DPDS. In addition, DPDS administration abated myeloperoxidase activity, tumour necrosis factor alpha and nitric oxide levels along with caspase-3 activity in doxorubicin-administered rats. Chemoprotection of doxorubicin-associated neurotoxicity by DPDS was further validated by histomorphometry and histochemical staining. Taken together, DPDS through offsetting of oxido-inflammatory stress and caspase-3 activation elicited neuroprotection in doxorubicin-treated rats., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human post-mortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human. [ABSTRACT FROM AUTHOR]

Treatment for Alzheimer's disease (AD) can be more effective in the early stages. Although we do not completely understand the aetiology of the early stages of AD, potential pathological factors (amyloid beta [Aβ] and tau) and other co-factors have been identified as causes of AD, which may indicate some of the mechanism at work in the early stages of AD. Today, one of the primary techniques used to help delay or prevent AD in the early stages involves alleviating the unwanted effects of oxidative stress on Aβ clearance. 4-Hydroxynonenal (HNE), a product of lipid peroxidation caused by oxidative stress, plays a key role in the adduction of the degrading proteases. This HNE employs a mechanism which decreases catalytic activity. This process ultimately impairs Aβ clearance. The degradation of HNE-modified proteins helps to alleviate the unwanted effects of oxidative stress. Having a clear understanding of the mechanisms associated with the degradation of the HNE-modified proteins is essential for the development of strategies and for alleviating the unwanted effects of oxidative stress. The strategies which could be employed to decrease the effects of oxidative stress include enhancing antioxidant activity, as well as the use of nanozymes and/or specific inhibitors. One area which shows promise in reducing oxidative stress is protein design. However, more research is needed to improve the effectiveness and accuracy of this technique. This paper discusses the interplay of potential pathological factors and AD. In particular, it focuses on the effect of oxidative stress on the expression of the Aβ-degrading proteases through adduction of the degrading proteases caused by HNE. The paper also elucidates other strategies that can be used to alleviate the unwanted effects of oxidative stress on Aβ clearance. To improve the effectiveness and accuracy of protein design, we explain the application of quantum mechanical/molecular mechanical approach. [ABSTRACT FROM AUTHOR]