scholarly journals RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Leticia Pérez-Sisqués ◽  
Anna Sancho-Balsells ◽  
Júlia Solana-Balaguer ◽  
Genís Campoy-Campos ◽  
Marcel Vives-Isern ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Mrna Levels ◽  
Spine Density ◽  
Memory Impairments ◽  
Protein Levels ◽  
Synaptic Markers ◽  
5Xfad Mice

AbstractRTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

DEF8 and Autophagy-Associated Genes are Altered in Mild Cognitive Impairment, Probable Alzheimer’s Disease Patients and a Transgenic Model of the Disease

2021 ◽  
pp. 1-16
Author(s):  
Esteban Leyton ◽  
Diego Matus ◽  
Sandra Espinoza ◽  
José Matías Benitez ◽  
Bastián I. Cortes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Real Time ◽  
Real Time Pcr ◽  
Mononuclear Cells ◽  
Differentially Expressed ◽  
Protein Levels ◽  
5Xfad Mice

Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer’s disease (AD). However, few studies are available concerning autophagy gene expression in AD patients. Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheral blood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. Method: By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence. Results: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization. Conclusion: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD.

scholarly journals Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Avijit Banik ◽  
Radhika Amaradhi ◽  
Daniel Lee ◽  
Michael Sau ◽  
Wenyi Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Complete Blood Count ◽  
Cardiovascular Effects ◽  
Mrna Levels ◽  
Proinflammatory Mediators ◽  
Model Of Alzheimer’S Disease ◽  
Cox 2 ◽  
5Xfad Mice

Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.

scholarly journals Absence of Thyroid Hormone Induced Delayed Dendritic Arborization in Mouse Primary Hippocampal Neurons Through Insufficient Expression of Brain-Derived Neurotrophic Factor

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroyuki Yajima ◽  
Izuki Amano ◽  
Sumiyasu Ishii ◽  
Tetsushi Sadakata ◽  
Wataru Miyazaki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Brain Derived Neurotrophic Factor ◽  
Mrna Levels ◽  
Protein Levels ◽  
Primary Hippocampal Neurons ◽  
Developmental Impairment

Thyroid hormone (TH) plays important roles in the developing brain. TH deficiency in early life leads to severe developmental impairment in the hippocampus. However, the mechanisms of TH action in the developing hippocampus are still largely unknown. In this study, we generated 3,5,3’-tri-iodo-l-thyronine (T3)-free neuronal supplement, based on the composition of neuronal supplement 21 (NS21), to examine the effect of TH in the developing hippocampus using primary cultured neurons. Effects of TH on neurons were compared between cultures in this T3-free culture medium (-T3 group) and a medium in which T3 was added (+T3 group). Morphometric analysis and RT-qPCR were performed on 7, 10, and 14 days in vitro (DIV). On 10 DIV, a decreased dendrite arborization in -T3 group was observed. Such difference was not observed on 7 and 14 DIV. Brain-derived neurotrophic factor (Bdnf) mRNA levels also decreased significantly in -T3 group on 10 DIV. We then confirmed protein levels of phosphorylated neurotrophic tyrosine kinase type 2 (NTRK2, TRKB), which is a receptor for BDNF, on 10 DIV by immunocytochemistry and Western blot analysis. Phosphorylated NTRK2 levels significantly decreased in -T3 group compared to +T3 group on 10 DIV. Considering the role of BDNF on neurodevelopment, we examined its involvement by adding BDNF on 8 and 9 DIV. Addition of 10 ng/ml BDNF recovered the suppressed dendrite arborization induced by T3 deficiency on 10 DIV. We show that the lack of TH induces a developmental delay in primary hippocampal neurons, likely caused through a decreased Bdnf expression. Thus, BDNF may play a role in TH-regulated dendritogenesis.

L1CAM Beneficially Inhibits Histone Deacetylase 2 Expression under Conditions of Alzheimer’s Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 382-392 ◽  
Author(s):  
Chengliang Hu ◽  
Junkai Hu ◽  
Xianghe Meng ◽  
Hongli Zhang ◽  
Huifan Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucocorticoid Receptor ◽  
Histone Deacetylase ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Extracellular Domain ◽  
Histone Deacetylase 2 ◽  
Protein Levels ◽  
Deficient Mice

Background: Cognitive capacities in Alzheimer’s Disease (AD) are impaired by an epigenetic blockade mediated by histone deacetylase 2 (HDAC2), which prevents the transcription of genes that are important for synaptic plasticity. Objective: Investigation of the functional relationship between cell adhesion molecule L1 and HDAC2 in AD. Methods: Cultures of dissociated cortical and hippocampal neurons from wild-type or L1-deficient mice were treated with Aβ1-42 for 24 h. After removal of Aβ1-42 cells were treated with the recombinant L1 extracellular domain (rL1) for 24 h followed by immunohistochemistry, western blotting, and reverse transcription PCR to evaluate the interaction between L1 and HDAC2. Results: Aβ and HDAC2 protein levels were increased in APPSWE/L1+/- mutant brains compared to APPSWE mutant brains. Administration of the recombinant extracellular domain of L1 to cultured cortical and hippocampal neurons reduced HDAC2 mRNA and protein levels. In parallel, reduced phosphorylation levels of glucocorticoid receptor 1 (GR1), which is implicated in regulating HDAC2 levels, was observed in response to L1 administration. Application of a glucocorticoid receptor inhibitor reduced Aβ-induced GR1 phosphorylation and prevented the increase in HDAC2 levels. HDAC2 protein levels were increased in cultured cortical neurons from L1-deficient mice. This change could be reversed by the administration of the recombinant extracellular domain of L1. Conclusion: Our results suggest that some functionally interdependent activities of L1 and HDAC2 contribute to ameliorating the phenotype of AD by GR1 dephosphorylation, which leads to reduced HDAC2 expression. The combined findings encourage further investigations on the beneficial effects of L1 in the treatment of AD.

Plant Compound Curcumin Mediates Calcineurin Activity to Upregulate ABCA1 Expression in a Model of Alzheimer’s Disease

2015 ◽  
Vol 1120-1121 ◽  
pp. 821-825
Author(s):  
Ke Xu ◽  
Xiong Zhang ◽  
Li Yu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Protein Levels ◽  
Atp Binding Cassette Transporter ◽  
Model Of Alzheimer’S Disease ◽  
Abca1 Expression ◽  
Underlying Mechanisms ◽  
Calcineurin Activity

Cholesterol metabolism plays an important role in pathogenesis of Alzheimer’s disease (AD). Curcumin has been reported to decrease cholesterol in serum through increasing the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) expression, but the underlying mechanisms are not fully understand yet. To investigate the effects of curcumin on the activity of calcineurin and the expression of ABCA1 in vitro, N2a/APP695swe cells were treated with curcumin at 5 umol/L for 24 h, or with the calcineurin activity inhabitor CyclosporinA (CsA) at 0.5 umol/L for 48 h. Our findings showed that curcumin could increase the expression of the ABCA1 at mRNA and protein levels, furthermore, it could inhibit the calcineurin activity, CsA also could increase the expression of the ABCA1 at mRNA and protein levels. These findings suggest that curcumin may upregulate the expression of ABCA1 via inhibiting the calcineurin activity in N2a/APP695swe cells.

scholarly journals Irisin Exerts Neuroprotective Effects on Cultured Neurons by Regulating Astrocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kexin Wang ◽  
Hongyan Li ◽  
Hongxing Wang ◽  
Jun-hui Wang ◽  
Feng Song ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Conditioned Medium ◽  
Hippocampal Neurons ◽  
Cell Damage ◽  
Future Application ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Amyloid Toxicity

Neurons suffer detrimental effects from β-amyloid toxicity in Alzheimer’s disease. The exercise hormone, irisin, is found to induce a neuroprotective gene program and facilitates the beneficial effects on cognitive function. But no effort is made to test its direct protective effects on neurons against the Aβ-induced cell toxicity so far. In the present study, we investigated whether irisin could protect neurons against Aβ- (25–35) induced cell damage and explored the possible underlying mechanisms. Primary cell cultures of astrocytes and neurons were established. Conditioned medium from astrocyte was collected for the treatment and biochemistry assay study. To explore the protein expression changes, Western blot and ELISA assays were used in these in vitro cell culture models. Exposure of hippocampal neurons to 10 μM Aβ (25–35) caused significant reduction on cell viability, and the toxic effect was not significantly reduced by the coadministration of irisin. However, pretreated astrocyte-conditioned medium with irisin for 12 hours notably protected the neurons from the toxicity of Aβ. Also, we found that irisin could attenuate the release of IL-6 and IL-1β from cultured astrocytes and decrease the expression level of COX-2 and phosphorylation of AKT. Last, we found that irisin could reduce NFκB activation in astrocyte exposed to Aβ by preventing the phosphorylation and the loss of IκBα. Our finding may provide novel evidence for the future application of irisin in the treatment of Alzheimer’s disease and the memory dysfunction in diabetes mellitus.

Neuroprotective effect of the hexapeptide HLDF-6 on rat hippocampal neurons on the in vivo and in vitro models of alzheimer’s disease

2006 ◽  
Vol 32 (4) ◽  
pp. 360-367 ◽  
Author(s):  
I. A. Kostanyan ◽  
S. S. Zhokhov ◽  
Z. I. Storozheva ◽  
A. T. Proshin ◽  
E. A. Surina ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Neuroprotective Effect ◽  
In Vitro Models

scholarly journals Platycodon grandiflorum Root Protects against Aβ-Induced Cognitive Dysfunction and Pathology in Female Models of Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 207
Author(s):  
Yunkwon Nam ◽  
Soo Jung Shin ◽  
Yong Ho Park ◽  
Min-Jeong Kim ◽  
Seong Gak Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Hippocampal Formation ◽  
Histopathological Analysis ◽  
Root Extract ◽  
Platycodon Grandiflorum ◽  
5Xfad Mice

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aβ) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that Platycodon grandiflorum root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aβ accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aβ related pathology and ameliorating Aβ induced cognitive impairment.

scholarly journals Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

2021 ◽  
Vol 15 ◽  
Author(s):  
Frances M. Potjewyd ◽  
Alison D. Axtman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
E3 Ligase ◽  
Amyloid Β ◽  
3D Cell Culture ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Protein Levels ◽  
Chemical Tools

The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.

Sign in / Sign up

Export Citation Format

Share Document