Altered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice.
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ABSTRACT:
SUBMITTER: Wilcox JM
PROVIDER: S-EPMC8457528 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeThe aim was to investigate the effect of APOE ε4 allele on cognitive decline in adAD. Presence of the APOE ε4 allele reduces age of symptom onset, increases disease progression, and lowers cognitive performance in sporadic Alzheimer's disease (AD), while the impact of the APOE ε4 allele in autosomal-dominant AD (adAD) is incompletely known.MethodsMutation carriers (MCs; n = 39) and non-carriers (NCs; n = 40) from six adAD families harbouring a mutation in the APP (28 MCs and 25 NCs) or the PSEN1 genes (11 MCs and 15 NCs) underwent repeated cognitive assessments. A timeline of disease course was defined as years to expected age of clinical onset (YECO) based on history of disease onset in each family. The MC and NC groups were comparable with regard to demographics and prevalence of the APOE ε4 allele. The relationship between cognitive decline and YECO, YECO2 , education, APOE, and APOE-by-YECO interaction was analysed using linear mixed-effects models.ResultsThe trajectory of cognitive decline was significantly predicted by linear and quadratic YECO and education in MCs and was determined by age and education in NCs. Adding APOE ε4 allele (presence/absence) as a predictor did not change the results in the MC and NC groups. The outcome also remained the same for MCs and NCs after adding the APOE-by-YECO interaction as a predictor. Analyses of APP and PSEN1 MCs separately showed favourable APOE-by-YECO interaction in APP (less steep decline) and unfavourable interaction in PSEN1 (steeper decline), linked to the APOE ε4 allele.ConclusionThe APOE ε4 allele influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with adAD, indicating a possible antagonistic pleiotropy.
| S-EPMC9826049 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfα, Cox2, p21, and Nox2, reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma β40- and β42-amyloid levels and altered hepatic but not brain expression of genes involved in β-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD.
| S-EPMC6572466 | biostudies-literature
Project description:Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 months, middle-aged F344 rats were fed diets containing low, medium (typical amount) or high vitamin D3 (100, 1000 or 10,000 IU/kg diet, respectively) and then hippocampal-dependent learning and memory were tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication and G-protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function and suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging. Sixty, middle-aged male F344 rats were divided into three groups, each receiving for 5-6 months a different dietary amount of cholecalciferol (vitamin D3; VitD3). Purified AIN-93G (Harlan-Teklad) diet was modified to contain low, medium or high VitD3 (IU/kg diet): High = 10,000, Standard (Control) = 1000; Low = 100. Animal weight and amount of food consumed was recorded 2-3 times/week. Serum levels of 25-hydroxy vitamin D were determined using liquid chromatography/tandem mass spectrometry (ZRT Laboratory). Hippocampal RNA was isolated, quantified and checked for RNA integrity. One low VitD3 sample failed RNA quality control. Remaining RNA samples were applied to Affymetrix Rat Gene 1.0 ST arrays (one array/subject). Pre-statistical filtering removed poorly annotated probe sets, low intensity signals, and outlier values (>2SD of the group mean). Filtered data were analyzed by 1-way ANOVA to identify significant differences and the False Discovery Rate (FDR) procedure was used to estimate the error of multiple testing. FDR was compared at 0.31 and 0.17. Significant genes were assigned to one of four idealized expression patterns using Pearson’s test and separated by the sign of their correlation; relative gene expression values are provided on the log-2 scale. Functional categorization for significant genes was determined using DAVID bioinformatic tools. Please note that 'Marked' and 'Unmarked' (in the sample titles) refers to whether the rat had a mark on its tail. The rats were pair-housed and this is how two rats in one cage were distinguished.
2014-09-23 | E-GEOD-61326 | biostudies-arrayexpress
Project description:Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aβ) aggregates. Aβ aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline.
| S-EPMC8069161 | biostudies-literature
Project description:Alzheimer's disease (AD) is characterized by a progressive memory decline and numerous pathological abnormalities, including amyloid ? (A?) accumulation in the brain and synaptic dysfunction. Here we wanted to study whether these brain changes were associated with alteration in the population of monocyte subsets since accumulating evidence supports the concept that the innate immune system plays a role in the etiology of this disease. We then determined the immune profile together with expression of genes encoding synaptic proteins and neurotrophins in APP(Swe)/PS1 mice and their age-matched wild-type (WT) littermates. We found that the progressive cognitive decline and the dramatic decrease in the expression of numerous synaptic markers and neurotrophins correlated with a major defect in the subset of circulating inflammatory monocytes. Indeed the number of CX(3)CR1(low)Ly6-C(high)CCR2(+)Gr1(+) monocytes remained essentially similar between 5 weeks and 6 months of age in APP(Swe)/PS1 mice, while these cells significantly increased in 6-month-old WT littermates. Of great interest is that the onset of cognitive decline was closely associated with the accumulation of soluble A?, disruption of synaptic activity, alteration in the BDNF system, and a defective production in the subset of CX(3)CR1(low)Ly6-C(high)CCR2(+)Gr1(+) monocytes. However, these memory impairments can be prevented or restored by boosting the monocytic production, using a short treatment of macrophage colony-stimulating factor (M-CSF). In conclusion, low CCR2(+) monocyte production by the hematopoietic system may be a direct biomarker of the cognitive decline in a context of AD.
| S-EPMC3485573 | biostudies-literature
Project description:This study assessed the extent to which high fat diet (HFD)-induced ?-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice. Insoluble ?-amyloid levels, and extent of tau phosphorylation were also lower following dietary reversal in APP/PSEN1 mice compared to high fat-fed animals, indicating that the inflammatory response may have contributed to key pathogenic pathways in the Alzheimer's disease model. The data suggest that weight loss can be a vital strategy for cognitive protection, but also highlight potential mechanisms for intervention when sustained weight loss is not possible.
| S-EPMC5316363 | biostudies-literature
Project description:BackgroundPerioperative neurocognitive disorders (PNDs) are considered the most common postoperative complication in geriatric patients. However, its pathogenesis is not fully understood. Surgery-triggered neuroinflammation is a major contributor to the development of PNDs. Neuroinflammation can influence N-methyl-D-aspartate receptor (NMDAR) expression or function which is closely associated with cognition. We, therefore, hypothesized that the persistent changes in NMDAR expression or function induced by transient neuroinflammation after surgery were involved in the development of PNDs.MethodsEighteen-month-old male Sprague-Dawley rats were subjected to abdominal surgery with sevoflurane anesthesia to establish the PNDs animal model. Then, we determined the transient neuroinflammation by detecting the protein levels of proinflammatory cytokines and microglia activation using ELISA, western blot, immunohistochemistry, and microglial morphological analysis from postoperative days 1-20. Persistent changes in NMDAR expression were determined by detecting the protein levels of NMDAR subunits from postoperative days 1-59. Subsequently, the dysfunction of synaptic NMDAR was evaluated by detecting the structural plasticity of dendritic spine using Golgi staining. Pull-down assay and western blot were used to detect the protein levels of Rac1-GTP, phosphor-cofilin, and Arp3, which contribute to the regulation of the structural plasticity of dendritic spine. Finally, glycyrrhizin, an anti-inflammatory agent, was administered to further explore the role of synaptic NMDAR dysfunction induced by transient neuroinflammation in the neuropathogenesis of PNDs.ResultsWe showed that transient neuroinflammation induced by surgery caused sustained downregulation of synaptic NR2A and NR2B subunits in the dorsal hippocampus and led to a selective long-term spatial memory deficit. Meanwhile, the detrimental effect of neuroinflammation on the function of synaptic NMDARs was shown by the impaired structural plasticity of dendritic spines and decreased activity of the Rac1 signaling pathways during learning. Furthermore, anti-inflammatory treatment reversed the downregulation and hypofunction of synaptic NR2A and NR2B and subsequently rescued the long-term spatial memory deficit.ConclusionsOur results identify sustained synaptic NR2A and NR2B downregulation and hypofunction induced by transient neuroinflammation following surgery as important contributors to the development of PNDs in elderly rats.
| S-EPMC9281167 | biostudies-literature
Project description:Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 months, middle-aged F344 rats were fed diets containing low, medium (typical amount) or high vitamin D3 (100, 1000 or 10,000 IU/kg diet, respectively) and then hippocampal-dependent learning and memory were tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication and G-protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function and suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.
2014-09-23 | GSE61326 | GEO
Project description:Amyloid-β peptide (Aβ) aggregation is the hallmark of Alzheimer's disease (AD). The imbalance between the production and clearance of Aβ results in the accumulation and aggregation of Aβ in the brain. Thus far, few drugs are available for AD treatment, but exercise has been recognized for its cognition-enhancing properties in AD patients. The underlying mechanisms remain unclear. Our recent study showed that long-term running exercise could activate the lysosomal function in the brains of mice. In this study, we investigated whether exercise could reduce Aβ accumulation by activating lysosomal function in APP/PSEN1 transgenic mice. Started at the age of 5 months, the mice were trained with a running wheel at the speed of 18 r/min, 40 min/d, 6 d/week for 5 months, and were killed at the end of the 10th month, then brain tissue was collected for biochemical analyses. The cognitive ability was assessed in the 9th month. We showed that long-term exercise significantly mitigated cognitive dysfunction in AD mice, accompanied by the enhanced lysosomal function and the clearance of Aβ in the brain. Exercise significantly promoted the nuclear translocation of transcription factor EB (TFEB), and increased the interaction between nuclear TFEB with AMPK-mediated acetyl-CoA synthetase 2, thus enhancing transcription of the genes associated with the biogenesis of lysosomes. Exercise also raised the levels of mature cathepsin D and cathepsin L, suggesting that more Aβ peptides could be degraded in the activated lysosomes. This study demonstrates that exercise may improve the cognitive dysfunction of AD by enhancing lysosomal function.
| S-EPMC8976063 | biostudies-literature
Project description:Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4-7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyperexcitability and network synchronization.
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