Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice

2022 ◽  
Author(s):  
Liuji Chen ◽  
Nawab John Dar ◽  
Ren Na ◽  
Kirsten Danae McLane ◽  
Kwangsun Yoo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
5Xfad Mice

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 Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment

2020 ◽  
Vol 21 (8) ◽  
pp. 2820 ◽  
Author(s):  
Na Kyung Lee ◽  
Hunnyun Kim ◽  
Jehoon Yang ◽  
Jeyun Kim ◽  
Jeong Pyo Son ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Disease Progression ◽  
Treatment Options ◽  
Neuronal Loss ◽  
Vascular Cognitive Impairment ◽  
Wild Type ◽  
Heterogeneous Nature ◽  
Vascular Compromise ◽  
5Xfad Mice ◽  
The Right

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer’s disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.

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 Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice

Aging ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 664-684 ◽  
Author(s):  
Christian Griñán-Ferré ◽  
Sara Sarroca ◽  
Aleksandra Ivanova ◽  
Dolors Puigoriol-Illamola ◽  
Fernando Aguado ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Alzheimer Disease ◽  
Epigenetic Mechanisms ◽  
5Xfad Mice

scholarly journals Front Cover: Green Tea Suppresses Amyloid β Levels and Alleviates Cognitive Impairment by Inhibiting APP Cleavage and Preventing Neurotoxicity in 5XFAD Mice

2021 ◽  
Vol 65 (19) ◽  
pp. 2170051
Author(s):  
Zhipeng Kan ◽  
Yijun Wang ◽  
Qian Chen ◽  
Xiaoyu Tang ◽  
Henry J. Thompson ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Green Tea ◽  
Amyloid Β ◽  
Front Cover ◽  
5Xfad Mice

scholarly journals Modulation of Neuroinflammation by Low-dose Radiation Therapy in an Animal Model of Alzheimer’s Disease 

2020 ◽  
Author(s):  
Eun-Jeong Yang ◽  
Hak Jae Kim ◽  
Jin Ho Kim ◽  
Jeongmin Yoon ◽  
Young-Seok Seo ◽  
...  
Keyword(s):  
Animal Model ◽  
Radiation Therapy ◽  
Cognitive Impairment ◽  
Inflammatory Cytokines ◽  
Late Stage ◽  
Low Dose ◽  
Low Dose Radiation ◽  
5Xfad Mice ◽  
Dose Radiation ◽  
Pro Inflammatory Cytokines

Abstract Background Recently, several studies have reported that low dose radiation therapy (RT) reduces the release of pro-inflammatory cytokines in inflammatory-degenerative disorders including Alzheimer’s disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Thus, low dose RT is expected to be used clinically for treating AD. However, the proper doses, effects, and underlying mechanisms of RT in AD have not been determined. Therefore, in this study, we aimed to determine the appropriate RT dose and schedule for AD treatment, and to investigate the therapeutic effects and mechanisms of low-dose RT in AD. MethodsWe first determined the proper dose and schedule of RT in late stage AD using 8–9-month old 5x familial AD(5xFAD) mice, a well-known animal model of AD, by comparing the effects of a low total dose with a low dose per fraction (LD-LDRT, 5 × 0.6 Gy) and a low-moderate total dose with a conventional dose per fraction (LMD-CDRT, 5 × 2 Gy). ResultsLD-LDRT and LMD-CDRT were found to reduce the level of pro-inflammatory cytokines, i.e. CD54, IL-3, CXCL9/10, and CCL2/4 in the hippocampus of 5xFAD mice. Further, increased microgliosis assessed with Iba-1 was significantly reduced by LD-LDRT in the hippocampus of 5xFAD mice. Moreover, LD-LDRT and LMD-CDRT decreased the amyloid plaque burden in 5xFAD mice and attenuated their cognitive impairment; these effects persisted for nearly one month. ConclusionsThe present study showed that LD-LDRT rescues cognitive impairment and prevents accumulation of amyloid plaques by regulating neuroinflammation in the late stage of AD, with an efficacy equivalent to that of LMD-CDRT. Furthermore, it suggests that LD-LDRT may facilitate accessible and convenient treatment in clinical trials compared to LMD-CDRT.

scholarly journals A selective p38α/β MAPKs inhibitor alleviates neuropathology and cognitive impairment by modulating microglia function in 5XFAD mouse

2020 ◽  
Author(s):  
Min Sung Gee ◽  
Seung Hwan Son ◽  
Seung Ho Jeon ◽  
Jimin Do ◽  
Namkwon Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Conditioned Medium ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
P38 Mapks

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be one of the important strategies for AD therapy. Previous efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. Especially, recent studies showed that pharmacological p38α MAPK inhibition improved memory impairment in AD mouse models. Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38α/β MAPKs inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR respectively. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and prevented spatial learning memory loss in 9-month-old 5XFAD mice. Interestingly, we found the decreased pro-inflammatory conditions and increased expression of alternatively activated microglial markers and microglial phagocytic receptors. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. Conclusion: Taken together, a selective p38α/β MAPKs inhibitor NJK14047 successfully showed therapeutic effects in 5XFAD mice. Our data support that p38 MAPKs inhibition is a potential strategy for AD therapy and NJK14047 might be one of the promising candidates for AD therapeutics targeting p38 MAPKs.

scholarly journals A selective p38α/β MAPKs inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

2020 ◽  
Author(s):  
Min Sung Gee ◽  
Seung Hwan Son ◽  
Seung Ho Jeon ◽  
Jimin Do ◽  
Namkwon Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
Mitogen Activated Protein ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
P38 Mapks

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods: In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPKs inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. Conclusion: Taken together, a selective p38α/β MAPKs inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPKs inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia

Sign in / Sign up

Export Citation Format

Share Document