A New Approach to Model Sporadic Alzheimer’s Disease by Intracerebroventricular Streptozotocin Injection in APP/PS1 Mice

Kelliny, Sally; Lin, Liying; Deng, Isaac; Xiong, Jing; Zhou, Fiona H.; Al‐Hawwas, Mohammed; Bobrovskaya, Larisa; Zhou, Xin‐Fu

doi:10.1007/s12035-021-02338-5

Cited by 11 publications

(5 citation statements)

References 87 publications

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“…Numerous studies have documented the increased prevalence of AD in patients with T2DM (Biessels & Despa, 2018; Norton et al, 2014), suggesting that diabetic pathologies exacerbate AD pathogenesis when AD and T2DM coexist. To explore the close relationship between these two diseases, various mixed animal models have been developed, including APP/PS1xdb/db, APPxob/ob, and APPxIAPP mice and high‐fat diet‐induced or streptozotocin‐induced diabetes in APP/PS1 mice (Ettcheto et al, 2021; Kelliny et al, 2021; Ramos‐Rodriguez et al, 2017; Takeda et al, 2010; Wijesekara et al, 2017). In the present study, a mixed mouse model (APP/PS1xdb/db mice) resulting from a cross between APP/PS1 and db/m mice was generated.…”

Section: Discussionmentioning

confidence: 99%

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease

Meng

Zhang

et al. 2022

Phytotherapy Research

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We have previously reported that Gypenoside LXXV (GP‐75), a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum, ameliorated cognitive deficits in db/db mice. In this study, we further investigated the beneficial effects on cognitive impairment in APP/PS1 mice and a mouse model of diabetic AD (APP/PS1xdb/db mice). Interestingly, intragastric administration of GP‐75 (40 mg/kg/day) for 3 months significantly attenuated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice. GP‐75 treatment markedly reduced the levels of glucose, HbA1c and insulin in serum and improved glucose tolerance and insulin sensitivity in APP/PS1xdb/db mice. Notably, GP‐75 treatment decreased the β‐amyloid (Aβ) burden, as measured by 11C‐PIB PET imaging. Importantly, GP‐75 treatment increased brain glucose uptake as measured by 18F‐FDG PET imaging. Moreover, GP‐75 treatment upregulated PPARγ and increased phosphorylation of Akt (Ser473) and GLUT4 expression levels but decreased phosphorylation of IRS‐1 (Ser616) in the hippocampi of both APP/PS1 and APP/PS1xdb/db mice. Furthermore, GP‐75‐induced increases in GLUT4 membrane translocation in primary hippocampal neurons from APP/PS1xdb/db mice was abolished by cotreatment with the selective PPARγ antagonist GW9662 or the PI3K inhibitor LY294002. In summary, GP‐75 ameliorated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice by enhancing glucose uptake via activation of the PPARγ/Akt/GLUT4 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease

Meng

Zhang

et al. 2022

Phytotherapy Research

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“…While the method of action of STZ within the brain remains unclear, this toxin-based approach can increase Aβ and p-tau neuropathology levels in rodent models of humanized Aβ or tau [ 180 - 182 ]. In AD animal models, STZ-ICV injection was found to worsen neuroinflammation, cognition deficits, and neuropathology [ 180 , 182 - 184 ]. However, BIR status has mostly been assessed by evidence of changes in the basal phosphorylation downstream INSR substrates without a direct insulin challenge [ 179 , 182 , 185 ].…”

Section: Tools To Study Birmentioning

confidence: 99%

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease

Rhea,

Leclerc,

Yassine

et al. 2023

Aging and disease

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Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer’s disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.

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“…This STZ-APP/PS1 dual model is a newer approach to treating memory impairment in mice. The strategy combines previously used STZ-induced dementia and a genetically modified transgenic model . Hence, it can be speculated that this model will generate a higher amount and resemblance of AD features and can be synergistic compared to individual STZ or APP/PS1 models.…”

Section: Novel Approaches For Ad Animal Modelmentioning

confidence: 99%

“…The strategy combines previously used STZ-induced dementia and a genetically modified transgenic model. 92 Hence, it can be speculated that this model will generate a higher amount and resemblance of AD features and can be synergistic compared to individual STZ or APP/PS1 models. Moreover, the characteristics of sporadic and familial AD will probably be overlapped in this newly created animal model.…”

Section: Novel Approaches For Ad Animal Modelmentioning

confidence: 99%

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

et al. 2022

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A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer’s disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.

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A New Approach to Model Sporadic Alzheimer’s Disease by Intracerebroventricular Streptozotocin Injection in APP/PS1 Mice

Cited by 11 publications

References 87 publications

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

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