Dataset Information

Reelin protects against amyloid ? toxicity in vivo.

ABSTRACT: Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and is the most common form of dementia in people over the age of 65 years. The predominant genetic risk factor for AD is the ?4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin enhances synaptic plasticity by binding to the multifunctional ApoE receptors apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr). We have previously shown that the presence of ApoE4 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid ? (A?) oligomer-induced synaptic toxicity in vitro. We showed that when Reelin was knocked out in adult mice, these mice behaved normally without overt learning or memory deficits. However, they were strikingly sensitive to amyloid-induced synaptic suppression and had profound memory and learning disabilities with very low amounts of amyloid deposition. Our findings highlight the physiological importance of Reelin in protecting the brain against A?-induced synaptic dysfunction and memory impairment.

SUBMITTER: Lane-Donovan C

PROVIDER: S-EPMC4652952 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Reelin protects against amyloid β toxicity in vivo.

Lane-Donovan Courtney C Philips Gary T GT Wasser Catherine R CR Durakoglugil Murat S MS Masiulis Irene I Upadhaya Ajeet A Pohlkamp Theresa T Coskun Cagil C Kotti Tiina T Steller Laura L Hammer Robert E RE Frotscher Michael M Bock Hans H HH Herz Joachim J

Science signaling 20150707 384

Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and is the most common form of dementia in people over the age of 65 years. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin enhances synaptic plasticity by binding to the multifunctional ApoE receptors apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr). We have previously shown that the presence of ApoE4 r ...[more]

PMID: 26152694

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Project description:Clioquinol (CQ) was widely used as oral antibiotic before being taken off the market in many countries in 1970, after it was linked to subacute myelo-optic neuropathy (SMON) in Japan, leading to vision loss with many patients left wheelchair-bound. The common pathology of CQ-associated SMON was reproduced in animals but none of the proposed modes of toxicity explained the restriction of CQ-induced SMON to Japan. Given a re-emergence of CQ and related analogues as neuroprotectants, it is crucial to understand the underlying mechanism of CQ-induced toxicity to prevent any potential CQ-associated risks to future patients. A small molecule screen to find drugs that induce mitochondrial dysfunction in vitro identified CQ and the structurally related 8-hydroxyquinoline (8-OHQ). Their mitochondrial liability, pro-oxidative and cytotoxic activity was subsequently confirmed in some cell lines but surprisingly not in others. Subsequent studies in isogenic cell lines demonstrated that the antioxidant protein NQO1 is differentially expressed in the cell lines tested and potently protects against CQ toxicity. CQ-induced reduction of cellular ATP levels, increased lipid peroxidation and elevated cell death was also attenuated by antioxidants, implicating oxidative stress as the core mechanism of CQ-induced toxicity. These in-vitro findings were replicated in zebrafish. Visual acuity in zebrafish larvae that do not express NQO1, was reduced by CQ in a dose-dependent manner, while CQ did not affect visual function in the adult zebrafish that express NQO1. Similarly, pharmacological inhibition of NQO1 activity resulted in CQ-induced oxidative stress in the retina and severe acute systemic toxicity in the adult fish. Given the much higher prevalence of the inactivating C609T NQO1 polymorphism in the Japanese population compared to the European population, the results of this study could for the first time indicate how the geographic restriction of SMON cases to Japan could be explained. Importantly, if CQ or its derivatives are to be used safely for the treatment of neurodegenerative diseases, it seems imperative that NQO1 levels and activity of prospective patients should be ascertained.

Project description:Liuwei Dihuang (LWDH), a classic Chinese medicinal formula, has been used to improve or restore declined functions related to aging and geriatric diseases, such as impaired mobility, vision, hearing, cognition and memory. Here, we report on the effect and possible mechanisms of LWDH mediated protection of ?-amyloid (A?) induced paralysis in Caenorhabditis elegans using ethanol extract (LWDH-EE) and water extract (LWDH-WE). Chemical profiling and quantitative analysis revealed the presence of different levels of bioactive components in these extracts. LWDH-WE was rich in polar components such as monosaccharide dimers and trimers, whereas LWDH-EE was enriched in terms of phenolic compounds such as gallic acid and paeonol. In vitro studies revealed higher DPPH radical scavenging activity for LWDH-EE as compared to that found for LWDH-WE. Neither LWDH-EE nor LWDH-WE were effective in inhibiting aggregation of A? in vitro. By contrast, LWDH-EE effectively delayed A? induced paralysis in the transgenic C. elegans (CL4176) model which expresses human A?1-42. Western blot revealed no treatment induced reduction in A? accumulation in CL4176 although a significant reduction was observed at an early stage with respect to ?-amyloid deposition in C. elegans strain CL2006 which constitutively expresses human A?1-42. In addition, LWDH-EE reduced in vivo reactive oxygen species (ROS) in C. elegans (CL4176) that correlated with increased survival of LWDH-EE treated N2 worms under juglone-induced oxidative stress. Analysis with GFP reporter strain TJ375 revealed increased expression of hsp16.2::GFP after thermal stress whereas a minute induction was observed for sod3::GFP. Quantitative gene expression analysis revealed that LWDH-EE repressed the expression of amy1 in CL4176 while up-regulating hsp16.2 induced by elevating temperature. Taken together, these results suggest that LWDH extracts, particularly LWDH-EE, alleviated ?-amyloid induced toxicity, in part, through up-regulation of heat shock protein, antioxidant activity and reduced ROS in C. elegans.

Dataset Information

Reelin protects against amyloid ? toxicity in vivo.

Publications

Reelin protects against amyloid β toxicity in vivo.

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