Age-dependent Decrease Research Articles

Prenatal Hypoxia Induces Premature Aging Accompanied by Impaired Function of the Glutamatergic System in Rat Hippocampus.

Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2weeks), adult (3months) and advanced (18months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180Torr, 5% O2, 3h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.

Transcription factors β-catenin and Hex in postnatal development of the rat adrenal cortex: implication in proliferation control

Transcriptional regulation of growth, maturation, and cell turnover in adrenal cortex during postnatal development has been significantly less studied than in embryonic period, while elucidation of factors mediating its normal postnatal morphogenesis could clarify mechanisms of tumorigenesis in adrenal cortex. Expression of transcription factors Hex, β-catenin, and Wnt signaling in the adrenal cortex of male pubertal and postpubertal Wistar rats were examined. Adrenal cortex morphology and hormone production during postnatal development were also studied. Adrenocortical zones demonstrated similar reduction of Ki-67-expressing cells, but different patterns of morphological and functional changes. Age-dependent decrease in percentage of cells with membrane localization of β-catenin and stable rate of cells with nuclear β-catenin, indicative of Wnt signaling activation, were revealed in each cortical zone. Nuclear β-catenin was not observed in immature areas of zona fasciculata. No association between Wnt signaling activation and rates of proliferation as well as changes in secretion of adrenocortical hormones was observed in postnatal development of rat adrenal cortex. Hex, known as antiproliferative factor, showed up-regulation of expression after puberty. Strong inverse correlations between ratio of Hex-positive cells and proliferating cells were found in zona glomerulosa and zona fasciculata. Zona reticularis demonstrated moderate correlation. Thus, these findings suggest a role for Hex in proliferation control during postnatal development of the rat adrenal cortex and possible implication of Hex down-regulation in adrenocortical dysplasia and neoplasia, which requires further study. Evaluation of Hex expression may also be considered a potent tool in assessment of cell proliferation in rat adrenal cortex.

Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease.Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aβ) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed.Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG).Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BackgroundCerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. MethodsQuantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. ResultsWe found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. ConclusionsOur findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

Age-related electrophysiological changes in mouse taste receptor cells.

What is the central question of this study? Loss of taste or inability to distinguish between different tastes progresses with age. The purpose was to evaluate the age-dependent changes in taste by studying the electrophysiological properties of taste receptor cells. What is the main finding and its importance? Ageing decreased the voltage-gated Na+ and K+ current densities of type III cells (sour and/or salt receptor cells) but did not affect the current densities in type II cells. At the peripheral levels, the excitability of type III cells was reduced due to ageing, which may affect the signal transduction to taste nerves. The loss of taste due to normal ageing in mammals is assumed to be caused by the ageing of taste receptor cells. We examined the electrophysiological properties of taste receptor cells in the fungiform taste buds of ∼20-month-old mice in situ and subsequently identified their cell types with immunological markers: the inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R3) for type II cells and a SNARE protein, synaptosomal-associated protein 25 (SNAP-25), for type III cells. Other cells are referred to as non-immunoreactive cells (non-IRCs). Cell types of some cells that could not be identified using cell-type markers were identified based on the electrophysiological feature of the respective cell types. All cell types generated action potentials and a variety of voltage-gated currents. The type II cells mainly expressed tetraethylammonium (TEA)-insensitive and slowly activating outwardly rectifying currents and generated tail currents in repolarization. In contrast, the type III cells expressed TEA-sensitive and faster activating K+ currents and did not generate tail currents. These cell type-specific characteristics of voltage-gated currents in ∼20-month-old mice were similar to their respective cell types in ∼2-month-old mice. Also, we showed an age-dependent decrease in Na+ and K+ current densities in type III cells and an age-dependent increase in outwardly rectifying current density in non-IRCs. Ageing did not affect the voltage-gated current densities in type II cells. The decreased Na+ and K+ current densities, i.e. the decreased excitability of type III cells, due to ageing may affect the signal transduction to taste nerves.

Single nuclei sequencing reveals novel insights into cardiac cell signatures in human pediatric dilated cardiopathy

Abstract The mechanism underlying dilated cardiomyopathy (DCM) in children without a known genetic disorder are unclear. In contrast to adult DCM patients, there is an unmet need for therapeutic options that improve survival in pediatric DCM. Therefore, we performed single nuclei RNA sequencing (snRNA-seq) from heart tissue obtained from children undergoing heart transplantation due to severe heart failure. We processed heart tissue from 6 children with DCM (EF: 18.67±2.11%) of an age of 0.5, 0.75, 5, 6, 12 and 13 years (y). After snRNA-seq, unsupervised clustering was performed identifying 8 major cell types, including cardiomyocytes (CM), fibroblasts (FB), endothelial cells, leukocytes, pericytes, smooth muscle cells, neuronal-like cells and an endothelial-fibroblast-like cluster. Relative numbers of FB clusters correlated with increasing age of the children which was clinically validated by measuring late enhancement (LE) with cardiac magnetic resonance imaging in 68 pediatric DCM patients. The mean age of patients with LE was 5.86±0.53y vs. 2.36±0.53y in patients without LE (p<0.05). Further analysis of unique highly expressed genes (DEGs) between the 3 age groups identified a profound alteration of gene expression in FB clusters. FBs of explants of <1y old patients showed high expression of anti-fibrotic, development and remodeling associated genes. In contrast, FBs of 12–13y old children highly expressed pro-fibrotic and FB activation associated genes as transforming growth factor beta binding protein (6.63 fold), cytochrome P450 1B1 (3.79 fold), and periostin (7.67 fold) (all p<0.05). Moreover, we observed a switch in collagen expression patterns and in thrombospondin isoforms (from THBS1 to THBS4). Furthermore, our analysis revealed most profound transcriptional changes in CMs. We identified a cluster of CMs with a pro-regenerative profile in <1y old patients, which could not be detected during adolescence. This CM cluster showed high expression of genes associated with proliferation (e.g. cyclin D2), glycolytic metabolism and anti-oxidant markers. Increased cyclin D2 was confirmed by immunostaining (1.43 fold higher in <1y vs. 12–13y). Since all of these gene expression patterns might be affected by the underlying disease of the pediatric heart recipients, we explored their expression in FBs and CMs of postnatal vs. adult mice. Importantly, we could recapitulate the vast majority of the findings from humans in the mice experiments. Together, these data demonstrate an age-dependent decrease in CM numbers concomitant with increased FBs in pediatric DCM. FBs of <1y old pediatric patients revealed a distinct collagen expression profile and showed lower levels of pro-fibrotic genes. CMs of <1y old donors where characterized with a regeneration enabling gene expression profile, which include pro-proliferative genes. The expression patterns of the CMs indicates, that regeneration might also occur in humans during the firs year of life. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Dr. Rolf M. Schwiete Stiftung, DZHK

Caenorhabditis elegans algn-2 Is Critical for Longevity Conferred by Enhanced Nonsense-Mediated mRNA Decay.

SummaryNonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. Here, we aimed at identifying NMD-modulating factors that are crucial for longevity in C. elegans by performing genetic screens. We showed that knocking down each of algn-2/asparagine-linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased the transcript levels of NMD targets. Among these, algn-2 exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan and for longevity caused by various genetic interventions. We further demonstrated that upregulation of ALGN-2 by inhibition of daf-2/insulin/IGF-1 receptor contributed to longevity in an NMD-dependent manner. Thus, algn-2, a positive regulator of NMD, plays a crucial role in longevity in C. elegans, likely by enhancing RNA surveillance. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan.

Age-Associated Pathology and Functional Outcomes After Hip Arthroscopy in Female Patients: Analysis With 2-Year Follow-up

Background: Previous research has demonstrated a statistically significant relationship between hip arthroscopy outcomes and age. Purpose: To investigate the link, if any, between hip arthroscopy outcomes and intraoperative pathology as well as with patient age and sex. Study Design: Cohort study; Level of evidence, 3. Methods: Of 272 female patients aged ≥14 years undergoing primary hip arthroscopy for femoroacetabular impingement between August 2010 and September 2017, and with 2-year patient-reported outcome scores, a total of 194 (71.3%) were included for final analysis. These patients were separated into 3 age-based cohorts: <30 years (n = 44), 30 to 45 years (n = 74), and >45 years (n = 76). Their data were then analyzed and compared with respect to patient characteristic information, intraoperative pathology, and functional outcome scores for statistical significance, which was set at P < .05. Results: When an analysis of variance was conducted for the 3 age groups at 2-year follow-up, there was a statistically significant difference for modified Hip Harris Score (P = .0003; <30 years, 88.26 ± 13.1 [mean ± SD]; 30-45 years, 82.68 ± 18.0; >45 years, 75.03 ± 19.5). The results of an analysis of variance comparing 2-year Non-arthritic Hip Score were also statistically significant (P = .0002; <30 years, 89.9 ± 13.7; 30-45 years, 85.8 ± 15.8; >45 years, 78.1 ± 17.2). Results of logistic regression demonstrated that the odds of a cam-type lesion decreased by 0.971 for every additional year in age among female patients. The odds of achieving the patient-acceptable symptomatic state decreased by a factor of 0.96 for each additional year in age (P < .0004). Conclusion: Surgical treatment of femoroacetabular impingement in females led to improved functional outcomes at 2 years of follow-up, although older female patients did worse after hip arthroscopy as compared with their younger counterparts. There may be an age-dependent decrease in incidence of cam-type lesions in female patients.

Abundance of P-Glycoprotein and Other Drug Transporters at the Human Blood-Brain Barrier in Alzheimer's Disease: A Quantitative Targeted Proteomic Study.

The human blood-brain barrier (BBB) transporter P-gp can efflux amyloid-β (Aβ) out of the central nervous system (CNS). Aβ is thought to be the causative agent for Alzheimer's disease (AD). Using positron emission tomography imaging, we have shown that BBB P-gp activity is reduced in AD, as quantified by the in vivo brain distribution of the P-gp probe [11 C]-verapamil. Therefore, the aim of this study was to determine whether this reduced BBB P-gp activity in AD was due to decreased P-gp abundance at the BBB. Using targeted proteomics, we quantified the abundance of P-gp and other drug transporters in gray matter brain microvessels isolated from 43 subjects with AD and 38 age-matched controls (AMCs) from regions affected by AD (hippocampus and the parietal lobe of the brain cortex) and not affected by AD (cerebellum). First, P-gp abundance was decreased in the BBB of the hippocampus vs. the cerebellum in both subjects with AD and AMCs, and therefore was not AD-related. In addition, gray matter BBB abundance of P-gp (and of other transporters) in the hippocampus and the parietal lobe was not different between AD and AMC. The gray matter BBB abundance of all drug transporters decreased with age, likely due to age-dependent decrease in the density of brain microvessels. Collectively, the observed reduced in vivo cerebral BBB P-gp activity in AD cannot be explained by reduced abundance of P-gp at the BBB. Nevertheless, the drug transporter abundance at the human gray matter BBB data provided here can be used to predict brain distribution of drugs targeted to treat CNS diseases, including AD.

Small airway loss in the physiologically ageing lung: a cross-sectional study in unused donor lungs

Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 μm), and micro-CT of extracted cores (resolution 10 μm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers. For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16-83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression β coefficients are calculated using linear regression and polynomial models. Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (β coefficient per decade -0·119, 95% CI -0·193 to -0·045; R2=0·29) and especially in airways smaller than 2·0 mm in diameter (-0·158, -0·233 to -0·084; R2=0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (-0·00781, -0·04409 to 0·02848; R2=0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (β coefficient per decade -2035, 95% CI -2818 to -1252; R2=0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, -0·57 to 13·45, R2=0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values. Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals. Research Foundation-Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health.

Renin-aldosterone system evaluation over four decades in an extended family with autosomal dominant pseudohypoaldosteronism due to a deletion in the NR3C2 gene

Renal pseudohypoaldosteronism (PHA1) is a mild form of an aldosterone-resistance syndrome caused by mutations in the NR3C2 gene that codes for the mineralocorticoid receptor (MR). The disease is inherited as an autosomal dominant trait characterized by signs and symptoms of salt-losing in infancy. Disease manifestations could be severe in infancy but improve after the age of 1–3 years. Some affected members are asymptomatic and remain so life-long. In this study, we report the identification of a large deletion in the NR3C2 gene (c.1897+1_1898−1)_(c.*2955+?)del in renal PHA1 patients from an extended family spanning four generations. We prospectively evaluated the plasma renin activity and serum aldosterone profiles over four decades in symptomatic and asymptomatic affected family members. The benefits of early diagnosis on the clinical outcome were assessed as well. The long-term follow-up showed an age-dependent decrease in both plasma renin activity and serum aldosterone levels over the years. However, aldosterone levels remain high life-long. Thus, levels of aldosterone are a reliable marker to detect asymptomatic family members. The diagnosis of the proposita led to early diagnosis and therapy in other affected family members, significantly mitigating the clinical course. Despite the extremely elevated serum aldosterone levels during pregnancy, affected pregnant women did not experience any ill effects. However, this should be verified by observations in other adult patients.

Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

ObjectiveNeuroaxonal damage is reflected by serum neurofilament light chain (sNfL) values in a variety of acute and degenerative diseases of the brain. The aim of this study was to investigate the impact of febrile and epileptic seizures on sNfL, serum copeptin, and prolactin levels in children compared with children with febrile infections without convulsions.MethodsA prospective cross-sectional study was performed in children aging 6 months to 5 years presenting with fever (controls, n = 61), febrile seizures (FS, n = 78), or epileptic seizures (ES, n = 16) at our emergency department. sNfL, copeptin, and prolactin were measured within a few hours after the event in addition to standard clinical, neurophysiological, and laboratory assessment. All children were followed up for at least 1 year after presentation concerning recurrent seizures.ResultsSerum copeptin values were on average 4.1-fold higher in FS and 3.2-fold higher in ES compared with controls (both p < 0.01). Serum prolactin values were on average 1.3-fold higher in FS compared with controls ( p < 0.01) and without difference between ES and controls. There was no significant difference of mean sNfL values (95% CI) between all three groups, FS 21.7 pg/ml (19.6–23.9), ES 17.7 pg/ml (13.8–21.6), and controls 23.4 pg/ml (19.2–27.4). In multivariable analysis, age was the most important predictor of sNfL, followed by sex and C reactive protein. Neither the duration of seizures nor the time elapsed from seizure onset to blood sampling had an impact on sNfL. None of the three biomarkers were related to recurrent seizures.SignificanceSerum neurofilament light is not elevated during short recovery time after FS when compared with children presenting febrile infections without seizures. We demonstrate an age-dependent decrease of sNfL from early childhood until school age. In contrast to sNfL levels, copeptin and prolactin serum levels are elevated after FS.

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.

Age-Dependent Decrease in the Induction of Regulatory T Cells Is Associated With Decreased Expression of RALDH2 in Mesenteric Lymph Node Dendritic Cells

A decline in immune function with aging has been reported. Regulatory T cell (Treg) induction is known to decrease with age, and elucidating the underlying mechanism is important for preventing age-related diseases due to age-related chronic inflammation. In the intestine, dendritic cells (DCs) play an important role in inducing Tregs specific to oral antigens, and they efficiently induce Tregs via production of retinoic acid (RA), a vitamin A metabolite, catalyzed by the enzyme retinaldehyde dehydrogenase 2 (RALDH2). We have previously reported that in the mesenteric lymph node (MLN), a secondary lymphoid tissue in which immune responses to oral antigens are induced, four DC subsets express different levels of CD11b, CD103, and PD-L1, and we have reported that the CD11b–CD103+PD-L1high subset expresses the highest levels of the RALDH2 gene and induces Tregs in vitro. We examined Treg induction in young and aged mice using a Treg induction model by administering a food antigen, and we found that antigen-specific Treg induction was decreased in aged mice. We further investigated the MLN DCs, and a significant decrease in RALDH2 gene expression was observed in MLN DCs from aged mice. As factors, we found that the proportion of the CD11b–CD103+PD-L1high subset was decreased in aged mice compared with that in young mice and that RALDH enzyme activity was decreased in the CD11b–CD103+PD-L1high and CD11b+CD103+PD-L1high subsets. Furthermore, analysis of the methylation of the RALDH2 gene promoter region revealed that CpG motifs were more methylated in the MLN DCs of aged mice, suggesting that RALDH2 expression was suppressed by epigenetic changes. Finally, we found that RA treatment tended to increase Treg induction. These results suggest that the regulation of RA production may be involved in the age-related decrease in antigen-specific Treg induction.

Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer's Disease.

Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. This study's aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD. Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye.

IgG Antibody Responses to the Aedes albopictus 34k2 Salivary Protein as Novel Candidate Marker of Human Exposure to the Tiger Mosquito.

Mosquitoes of the Aedes genus transmit arboviruses of great importance to human health as dengue, chikungunya, Zika and yellow fever. The tiger mosquito Aedes albopictus can play an important role as arboviral vector, especially when Aedes aegypti is absent or present at low levels. Remarkably, the rapid worldwide spreading of the tiger mosquito is expanding the risk of arboviral transmission also to temperate areas, and the autochthonous cases of chikungunya, dengue and Zika in Europe emphasize the need for improved monitoring and control. Proteomic and transcriptomic studies on blood feeding arthropod salivary proteins paved the way toward the exploitation of genus-specific mosquito salivary proteins for the development of novel tools to evaluate human exposure to mosquito bites. We previously found that the culicine-specific 34k2 salivary protein from Ae. albopictus (al34k2) evokes specific IgG responses in experimentally exposed mice, and provided preliminary evidence of its immunogenicity to humans. In this study we measured IgG responses to al34k2 and to Ae. albopictus salivary gland protein extracts (SGE) in individuals naturally exposed to the tiger mosquito. Sera were collected in two areas of Northeast Italy (Padova and Belluno) during two different time periods: at the end of the low- and shortly after the high-density mosquito seasons. Anti-SGE and anti-al34k2 IgG levels increased after the summer period of exposure to mosquito bites and were higher in Padova as compared to Belluno. An age-dependent decrease of anti-saliva IgG responses was found especially in Padova, an area with at least 25 years history of Ae. albopictus colonization. Moreover, a weak correlation between anti-saliva IgG levels and individual perception of mosquito bites by study participants was found. Finally, determination of anti-al34k2 IgG1 and IgG4 levels indicated a large predominance of IgG1 antibodies. Overall, this study provides a convincing indication that antibody responses to al34k2 may be regarded as a reliable candidate marker to detect temporal and/or spatial variation of human exposure to Ae. albopictus; a serological tool of this kind may prove useful both for epidemiological studies and to estimate the effectiveness of anti-vectorial measures.

Aging impairs perceptual decision-making in mice: integrating computational and neurobiological approaches.

Decision-making is one of the cognitive domains which has been under-investigated in animal models of cognitive aging along with its neurobiological correlates. This study investigated the latent variables of the decision process using the hierarchical drift-diffusion model (HDDM). Neurobiological correlates of these processes were examined via immunohistochemistry. Young (n = 11, 4months old), adult (n = 10, 10months old), and old (n = 10, 18months old) mice were tested in a perceptual decision-making task (i.e. two-alternative forced-choice; 2AFC). Observed data showed that there was an age-dependent decrease in the accuracy rate of old mice while response times were comparable between age groups. HDDM results revealed that age-dependent accuracy difference was a result of a decrease in the quality of evidence integration during decision-making. Significant positive correlations observed between evidence integration rate and the number of tyrosine hydroxylase positive (TH+) neurons in the ventral tegmental area (VTA) and axon terminals in dorsomedial striatum (DMS) suggest that decrease in the quality of evidence integration in aging is related to decreased function of mesocortical and nigrostriatal dopamine.

Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation.

The COVID‐19 coronavirus is now spreading worldwide. Its pathogen, SARS‐CoV‐2, has been shown to use angiotensin‐converting enzyme 2 (ACE2) as its host cell receptor, same as the severe acute respiratory syndrome coronavirus (SARS‐CoV) in 2003. Epidemiology studies found males although only slightly more likely to be infected than females account for the majority of the severely ill and fatality, which also bias for people older than 60 years or with metabolic and cardiovascular diseases. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found a significantly higher level in Asian females, an age‐dependent decrease in all ethnic groups, and a highly significant decrease in type II diabetic patients of ACE2 expression. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. A shockingly common enrichment of viral infection pathways was found among ACE2 anti‐expressed genes, and multiple binding sites of virus infection related transcription factors and sex hormone receptors locate at ACE2 regulatory regions. Human and mice data analysis further revealed ACE2 expression is reduced in T2D patients and with inflammatory cytokine treatment and upregulated by estrogen and androgen (both decrease with age). Our findings revealed a negative correlation between ACE2 expression and COVID‐19 fatality at both population and molecular levels. These results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general.

Utility of Easy Z-Score Imaging System-Assisted SPECT in Detecting Onset Age-Dependent Decreases in Cerebral Blood Flow in the Posterior Cingulate Cortex, Precuneus, and Parietal Lobe in Alzheimer’s Disease with Amyloid Accumulation

Background: Easy Z-score imaging system (eZIS)-assisted SPECT accurately detects decreases in cerebral blood flow in the posterior cingulate cortex (PCC), precuneus, and parietal lobe, the cerebral regions deeply implicated in Alzheimer’s disease (AD). Several studies suggested onset age-dependent decreases in cerebral blood flow in these regions in AD, but these studies did not screen for amyloid accumulation, suggesting inclusion of non-AD patients in their subjects. Objective: By applying eZIS-SPECT to patients with amyloid deposition, it was the aim of this study to clarify onset age-dependent decreases in cerebral blood flow in the regions critical to AD. Methods: We retrospectively analyzed eZIS-SPECT data on 34 AD patients with amyloid retention confirmed by ¹¹C-Pittsburgh compound B-PET. The subjects were divided into an early-onset group (n = 16) and a late-onset group (n = 18). The three indicators of the eZIS that had discriminated between AD patients and normal controls in previous studies were compared between the two groups. Results: The mean values for the respective indicators were significantly higher in the early-onset group than in the late-onset group. Also, the proportion of patients with abnormalities in all indicators was significantly higher in the early-onset group (93.8%) than in the late-onset group (50.0%). Conclusions: The present study, applying eZIS-SPECT to amyloid-positive AD patients, suggests that reduced cerebral blood flow in the PCC, precuneus, and parietal lobe is more pronounced in the early-onset type than in the late-onset type of the disease.