Research ArticleNeurodegeneration

Reelin protects against amyloid β toxicity in vivo

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Science Signaling  07 Jul 2015:
Vol. 8, Issue 384, pp. ra67
DOI: 10.1126/scisignal.aaa6674

Protecting neurons from amyloid β

In the developing nervous system, the secreted protein Reelin helps to guide migrating neurons to their correct destination. In the adult nervous system, Reelin enhances synaptic plasticity and protects isolated neurons from the toxicity of amyloid β, the accumulation of which causes the neurodegeneration characteristic of Alzheimer’s disease. To avoid the developmental defects associated with Reelin deficiency, Lane-Donovan et al. generated mice with an inducible knockout of Reelin that accumulated amyloid β. Mice that lacked Reelin as adults showed greater defects in synaptic plasticity, learning, and memory in response to amyloid β accumulation, indicating that Reelin protects against the neurotoxicity of amyloid β in vivo.


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 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid β (Aβ) 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 Aβ-induced synaptic dysfunction and memory impairment.

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