Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice

Sun, Huan; Liu, Mengying; Sun, Tao; Chen, Yutong; Zhen, Linlin; Lian, Biyao; Zhao, Caidan; Li, Zhi; Zhang, Jiqiang; Liu, Yan

doi:10.1016/j.bbr.2019.112182

Cited by 25 publications

(17 citation statements)

References 41 publications

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“…AD is a disease with cognitive impairment as its clinical manifestation. In experiments with AD animal models, the MWM assay is commonly used to detect the learning ability and memory of the animals (Baeta-Corral and Giménez-Llort, 2015; Gong et al, 2019;Sun et al, 2019). In this study, APP/PS1 doubletransgenic mice and Aβ 25-35 -injected mice were subjected to the MWM test, and they had obvious cognitive dysfunction, consistent with the behavioral phenotype of the AD animal model (Tian et al, 2019).…”

Section: Discussionmentioning

confidence: 68%

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

Zhou

Deng

Zhao

et al. 2021

Front. Aging Neurosci.

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The pathogenesis of Alzheimer’s disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aβ25–35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ25–35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ25–35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.

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Section: Discussionmentioning

confidence: 68%

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

Zhou

Deng

Zhao

et al. 2021

Front. Aging Neurosci.

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“…Another proteolytic processing pathway is non-amyloidogenic pathway in which APP is cleaved by α-secretase and γ-secretase (Haass et al, 2012;Barage and Sonawane, 2015). In the specimens of AD patients and the APP/PS1 double transgenic mouse model, the α-secretase of the non-amyloidogenic pathway of APP is decreased, and the β-secretase of the amyloidogenic pathway of APP is increased, and the Aβ-degrading enzyme is decreased, which could lead to an imbalance in the production and degradation of Aβ (Holsinger et al, 2002;Kummer et al, 2012;Sogorb-Esteve et al, 2018;Yang et al, 2018;Sun et al, 2019b). Our results showed that Aβ 42 level in the ADT group was significantly lower than that in the AD group.…”

Section: Discussionmentioning

confidence: 99%

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aβ42 Burden at the Early Stage of Alzheimer’s Disease in APP/PS1 Transgenic Mice

Luo

Yang

et al. 2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease. Intervention in the early stage of AD is a new path for AD treatment that is being explored. The behavioral and pathological effects of anodal transcranial direct current stimulation (AtDCS) at the early stage of AD in the mouse model, amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, were investigated based on our previous studies. Thirty-three 6-month-old male APP/PS1 mice were randomly divided into the model group (AD group), model + sham stimulation group (ADST group) and stimulation group (ADT group). Eleven 6-month-old male C57 wild-type mice were randomly selected as a control group (CTL group). The ADT group received 10 AtDCS sessions. The Morris water maze (MWM) task and novel object recognition (NOR) task were used to test mouse memory. Nissl staining, Western blot (WB), immunohistochemistry and immunofluorescence staining of β-amyloid (Aβ 42), glial fibrillary acidic protein (GFAP) and NF200 were conducted for pathological analysis. The ADT group and the CTL group had a shorter escape latency and more platform-region crossings than the AD group and ADST group in the MWM. There was no significant difference in the discrimination index among the groups in the NOR task. Pathological analysis showed visible differences between the AD group and ADT group. This study revealed that earlystage APP/PS1 transgenic mice did not show recognition memory impairment. AtDCS effectively improved spatial learning and memory in the early-stage APP/PS1 transgenic mouse model of AD, alleviating Aβ burden and having a protective effect on neurons. AtDCS could improve AD-related symptoms by activating many glial cells to promote the degradation and clearance of Aβ or directly affecting production and degradation of Aβ to reduce glial activation. AtDCS is an effective means of early intervention in the early stage of AD.

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“…As we found that acetylation was able to stabilize AMPARs and rescue the effect of Aβ treatment in vitro , we wanted to know the role AMPAR acetylation plays in vivo and in AD conditions. As a widely used model of AD, the APP/PS1 mouse produces high levels of Aβ in the brain and demonstrates typical molecular and behavioral phenotypes of AD ( McClean and Hölscher, 2014 ; Reinders et al., 2016 ; Reiserer et al., 2007 ; Sun et al., 2019 ; Trinchese et al., 2004 ). To determine whether AMPAR acetylation is altered in this AD animal model, we isolated GluA1 from hippocampal brain tissues of 11-month-old APP/PS1 mouse by immunoprecipitation and probed for acetylation and ubiquitination ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

“…A reduction in AMPAR synaptic accumulation and the consequential suppression in synaptic strength is believed to be an early pathobiology in AD ( Baglietto-Vargas et al., 2018 ; Hsieh et al., 2006 ; Kamenetz et al., 2003 ; Li et al., 2019 ; Lin et al., 2019 ; Sun et al., 2019 ; Ting et al., 2007 ). We therefore wanted to know whether stabilization of AMPARs by acetylation confers positive effects toward AD conditions.…”

Section: Resultsmentioning

confidence: 99%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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Summary In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

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Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice

Cited by 25 publications

References 41 publications

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aβ42 Burden at the Early Stage of Alzheimer’s Disease in APP/PS1 Transgenic Mice

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

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