The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease

Cuchillo-Ibáñez, Inmaculada; Mata-Balaguer, Trinidad; Balmaceda, Valeria; Arranz, Juan José; Nimpf, Johannes; Sáez‐Valero, Javier

doi:10.1038/srep31646

Cited by 46 publications

(45 citation statements)

References 52 publications

(79 reference statements)

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“…Reelin levels present in the cerebrospinal fluid are altered in AD patients [ 116 ]. In contrast to reports that Reelin levels are diminished in AD (see above), Reelin mRNA and protein levels were reported to be increased in human AD brains, but Reelin signaling is impaired through amyloid β-mediated disruption of Reelin homodimers [ 117 , 118 , 119 ]. In aged animals, Reelin was shown to accumulate within amyloid-like deposits and this effect was significantly accerelated in AD mice [ 120 , 121 ].…”

Section: Reelin Apoer2 and Vldlr In Alzheimer’s Diseasecontrasting

confidence: 82%

The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

Dlugosz

Nimpf

2018

IJMS

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Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer’s disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.

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Section: Reelin Apoer2 and Vldlr In Alzheimer’s Diseasecontrasting

confidence: 82%

The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

Dlugosz

Nimpf

2018

IJMS

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“…Their blots show the full-length reelin protein and two proteolytic fragments (310 and 180 kDa). In our experience, the presence of abundant levels of the 180-kDa fragment may be a sign of reelin degradation in blood; whereas in brain extracts this fragment is abundant (17). Reelin in human plasma is sensitive to proteolysis, freeze-thawing and heating during long-term storage (18,19).…”

Section: Discussionmentioning

confidence: 80%

“…In children with autism (2-14 years), genetic pathways regulating cortical patterning, cell number and differentiation are dysregulated, whereas in adults with autism (15-56 years), dysregulation affects signalling, and repair pathways (11). In adults with autism, reelin expression is lower in prefrontal cortex, frontal cortex, temporal cortex, and cerebellum [ (11,15,17,18), Table 1]. Thus, it would be important to determine if these increments in plasma reelin levels represent a transient phenomenon from childhood to adulthood that could be controlled by reversible mechanisms, such as epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

Elevated Plasma Reelin Levels in Children With Autism

et al. 2020

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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders involving age-dependent gene dysregulation. Reelin is a glycoprotein that varies its expression throughout lifetime and controls cortical patterning and synaptogenesis. Brain and plasma reelin levels have been reported to be low in adults with autism; as well as in children with autism, but only when compared to control adults. Therefore, reelin expression levels in children with autism are unclear. For this reason, we compared plasma reelin levels in children with autism and children without autism (non-ASD) of similar ages to evaluate reelin expression in ASD during childhood. Plasma samples from 19 non-ASD (8.9 ± 0.8 years) and 40 children with autism (7.5 ± 0.5 years) were analyzed. We found that 50% of the children with autism displayed similar plasma reelin levels to the non-ASD group. However, the remaining 50% expressed more than 30 times more reelin compared to non-ASD levels. We also show that male children with autism displayed significantly higher reelin levels than females. The clinical presentation of this subgroup could not be distinguished from that of children with autism. Epilepsy or attention-deficit/hyperactivity disorder (ADHD) was not associated to reelin levels. We conclude that the high levels of plasma reelin might be an important hallmark in a subset of children with autism, previously unnoticed. As we could not find any correlation between reelin levels and ASD clinical presentations, our results may indicate transient reelin increases in the plasma or the characterization of a group of ASD individuals with a different pathophysiology.

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“…Increasing Aβ load deregulates Reelin-mediated ApoER2 signaling 98 during synaptic plasticity [71][72][73][74][75] but this might also alter Reelin's function on brain vessel dilation and functional hyperemia, thereby affecting memory function via multiple mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network

Vandal

Gunn

Institóris

et al. 2020

Preprint

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Cerebrovascular dysfunction is increasingly recognized as a major contributor to Alzheimer’s disease (AD). CD2-associated protein (CD2AP), an important predisposing factor for the disease, is enriched in the brain endothelium but the function of protein in the brain vasculature remains undefined. Here, we report that lower levels of CD2AP in brain vessels of human AD volunteers are associated with cognitive deficits. In awake mice, we show that brain endothelial CD2AP regulates cerebral blood flow during resting state and functional hyperemia. In the endothelium, CD2AP controls the levels and signaling of apolipoprotein E receptor 2 (ApoER2), a receptor activated by Reelin glycoprotein that is linked to memory function. Further, Reelin promotes brain vessel dilation and functional hyperemia and both effects are modulated by endothelial CD2AP. Finally, lower levels of ApoER2 in brain vessels are associated with vascular defects and cognitive dysfunction in AD individuals. Thus, deregulation of CD2AP impairs neurovascular coupling and harnessing the biology of the Reelin-ApoER2-CD2AP signaling axis in the brain endothelium may improve brain vascular dysfunction in AD patients.

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The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease

Cited by 46 publications

References 52 publications

The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

Elevated Plasma Reelin Levels in Children With Autism

The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network

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