Age-dependent behavioral and biochemical characterization of single APP knock-in mouse (APPNL-G-F/NL-G-F) model of Alzheimer's disease

Mehla, Jogender; Lacoursiere, Sean G.; Lapointe, Valérie; McNaughton, Bruce L.; Sutherland, Robert J.; McDonald, Robert J.; Mohajerani, Majid H.

doi:10.1016/j.neurobiolaging.2018.10.026

Cited by 99 publications

(155 citation statements)

References 59 publications

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“…This mouse model has the NL-G-F mutations in the amyloid precursor protein knocked-in to a C57BL genomic background, with each mutation contributing to an increased severity and speed manifestation of the disease (21). The combined effect of the APPNL−G−F mutations results in mice that experience rapid onset of AD-like symptoms at approximately 6 months (21). This is exactly the time point that we observed the massive hyper-activation of B2…”

Section: Discussionmentioning

confidence: 53%

“…In this study, we employed a mouse model of amyloid pathology in order to test the impact of increased amyloid beta load on B2 RNA processing in vivo. This mouse model has the NL-G-F mutations in the amyloid precursor protein knocked-in to a C57BL genomic background, with each mutation contributing to an increased severity and speed manifestation of the disease (21). The combined effect of the APPNL−G−F mutations results in mice that experience rapid onset of AD-like symptoms at approximately 6 months (21).…”

Section: Discussionmentioning

confidence: 99%

“…To test whether B2-SRGs are indeed de-regulated in amyloid pathology, we employed a transgenic mouse model of amyloid pathology, APP NL-G-F , (20) and the respective wild type control (C57BL/6J). The same animal cohorts that were previously characterized through a battery of immunohistochemistry (IHC) and behavioral tests (21) were used to isolate whole hippocampi for the transcriptome analysis conducted in the current study. Fig.2A depicts our experimental design while Fig.2B depicts the amyloid plaque deposition in the brains.…”

Section: A Number Of B2-srgs Get Hyper-activated During the Neurodegementioning

confidence: 99%

“…Fig.2A depicts our experimental design while Fig.2B depicts the amyloid plaque deposition in the brains. The behavioral tests in these mouse cohorts are presented in our previous study (21).…”

Section: A Number Of B2-srgs Get Hyper-activated During the Neurodegementioning

confidence: 99%

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Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology

Cheng

Saville

Gollen

et al. 2020

eLife

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The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer’s disease (AD).

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: A Number Of B2-srgs Get Hyper-activated During the Neurodegementioning

confidence: 99%

Section: A Number Of B2-srgs Get Hyper-activated During the Neurodegementioning

confidence: 99%

See 2 more Smart Citations

Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology

Cheng

Saville

Gollen

et al. 2020

eLife

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“…8,20 A tank was filled to a depth of 40 cm with water and made opaque by adding nontoxic white tempera paint. 8,20 A tank was filled to a depth of 40 cm with water and made opaque by adding nontoxic white tempera paint.…”

Section: Behavioural Testingmentioning

confidence: 99%

Cistanches alleviates sevoflurane‐induced cognitive dysfunction by regulating PPAR‐γ‐dependent antioxidant and anti‐inflammatory in rats

Peng

Liu

et al. 2019

J Cellular Molecular Medi

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This study aimed to investigate the protective effects and underlying mechanisms of cistanche on sevoflurane-induced aged cognitive dysfunction rat model. Aged (24 months) male SD rats were randomly assigned to four groups: control group, sevoflurane group, control + cistanche and sevoflurane + cistanche group. Subsequently, inflammatory cytokine levels were measured by ELISA, and the cognitive dysfunction of rats was evaluated by water maze test, open-field test and the fear conditioning test. Three days following anaesthesia, the rats were killed and hippocampus was harvested for the analysis of relative biomolecules. The oxidative stress level was indicated as nitrite and MDA concentration, along with the SOD and CAT activity.Finally, PPAR-γ antagonist was used to explore the mechanism of cistanche in vivo.The results showed that after inhaling the sevoflurane, 24-but not 3-month-old male SD rats developed obvious cognitive impairments in the behaviour test 3 days after anaesthesia. Intraperitoneal injection of cistanche at the dose of 50 mg/kg for 3 consecutive days before anaesthesia alleviated the sevoflurane-induced elevation of neuroinflammation levels and significantly attenuated the hippocampus-dependent memory impairments in 24-month-old rats. Cistanche also reduced the oxidative stress by decreasing nitrite and MDA while increasing the SOD and CAT activity.Moreover, such treatment also inhibited the activation of microglia. In addition, we demonstrated that PPAR-γ inhibition conversely alleviated cistanche-induced protective effect. Taken together, we demonstrated that cistanche can exert antioxidant, anti-inflammatory, anti-apoptosis and anti-activation of microglia effects on the development of sevoflurane-induced cognitive dysfunction by activating PPAR-γ signalling. K E Y W O R D Scistanche, postoperative cognitive dysfunction (POCD), PPAR-γ, sevoflurane

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Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long‐Term Cognitive Deficits

Diwan,

Mehla,

Nelson

et al. 2024

Advanced Science

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Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long‐term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long‐term clinical ramifications of SAH – especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced significant and trackable long‐term cognitive deficits. SAH is induced by performing double blood injections into the prechiasmatic cistern – a simple modification to the well‐characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients, including cerebral edema measured by MRI ‐ an indicator of early brain injury (EBI), neuroinflammation, apoptosis, and long‐term cognitive impairment. This newly developed SAH mouse model is considered an ideal paradigm for investigating the complex SAH pathophysiology and identifying novel druggable therapeutic targets for treating SAH severity and SAH‐associated long‐term neurocognitive deficits in patients.

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Age-dependent behavioral and biochemical characterization of single APP knock-in mouse (APPNL-G-F/NL-G-F) model of Alzheimer's disease

Cited by 99 publications

References 59 publications

Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology

Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology

Cistanches alleviates sevoflurane‐induced cognitive dysfunction by regulating PPAR‐γ‐dependent antioxidant and anti‐inflammatory in rats

Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long‐Term Cognitive Deficits

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