Reelin protects against amyloid β toxicity in vivo

Abstract

Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and the most common form of dementia in people over the age of 65. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin, which is a physiological ligand for the multifunctional ApoE receptors Apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr), enhances synaptic plasticity. 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. Here, we show 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 at 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.

Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation

“…Mice carrying the loxP-targeted Reln gene (which encodes the protein Reelin) were generated by gene targeting murine SV129J ES cells as described previously (15) and mated with Ldlr −/− (28) mice to yield double homozygotes ( Reln fl/fl ;Ldlr −/− ). Reelin fl/fl ;Ldlr −/− mice were then crossbred with CAG-Cre ETR2 mice (Jackson strain # 004682) to obtain CAG-Cre + Reelin fl/fl ;Ldlr −/− mice and their Cre-negative littermates.…”

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

“…This is partially due to the fact that ApoE expression, in both mice and humans, begins relatively late in development [46, 47]. Additionally, adult loss of Reelin and ApoE receptor signaling in mice is well-tolerated in the absence of amyloid pathology, likely due to homeostatic regulation and compensation by other neuromodulatory mechanisms [42]. …”

“…Previously, it was difficult to examine this protective role of Reelin in vivo , due to the necessity of Reelin in brain development; however, a conditional knockout mouse was recently developed to overcome these challenges. It was found that while adult loss of Reelin does not cause significant cognitive impairment - suggesting an ability of a healthy CNS to homeostatically compensate for Reelin loss - overexpression of Aβ in Reelin-deficient mice leaves them heavily impaired in the Morris Water maze task of learning and memory [42]. These findings highlight the important role for Reelin and ApoE receptor signaling in protecting the synapse from Aβ-induced suppression.…”

Embryonic mosaic deletion of APP results in displaced Reelin-expressing cells in the cerebral cortex

“…Previous studies have interrogated the effects of Reelin expression on levels of APP in different model systems [25–29]. In addition, connections between Aβ and Reelin have been shown, including effects of Aβ on Reelin signaling [30] and effects of Reelin on Aβ fibril formation and toxicity [31–32]. While reports differ on the directionality of these effects in different models, there is consensus that these two proteins interact biochemically.…”