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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Publications

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: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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