Reelin in Alzheimer’s Disease, Increased Levels but Impaired Signaling: When More is Less

Cuchillo-Ibáñez, Inmaculada; Balmaceda, Valeria; Mata-Balaguer, Trinidad; López-Font, Inmaculada; Sáez‐Valero, Javier

doi:10.3233/jad-151193

Cited by 34 publications

(26 citation statements)

References 143 publications

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“…Another consequence of the lesser reelin levels in AD-ApoE4 carriers is the difficulty of interpreting altered reelin expression in various AD cohorts if the APOE genotype is not investigated. Although we previously found increased reelin associated to AD in various cohorts, we also noted large intersubject variability in reelin protein and mRNA levels, and reports from other laboratories have been controversial regarding reelin changes in AD; now, in the light of our results, these differences could be explained by the presence or lack of the APOE-e4 allele (discussed in Cuchillo-Ibañez et al 43).…”

Section: Discussionsupporting

confidence: 45%

“…Alterations in reelin levels can contribute to the progression of AD pathology (49) and probably affect the capacity of reelin to protect against Ab toxicity (50,51). The crosstalk between APP/Ab and reelin has been shown by various groups, but the effect of Ab on reelin function should be considered when interpreting changes in expression in AD (discussed in Cuchillo-Ibañez et al 43).…”

Section: Discussionmentioning

confidence: 99%

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Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

et al. 2018

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Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The β-amyloid (Aβ) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aβ aa 1-42 (Aβ) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Aβ decreased nuclear levels of DNA-methyltransferase 1. However, RELN promoter methylation did not change in Aβ-treated cells or in AD brain extracts. Instead, the levels of ApoER2-CTF appeared significantly lower in Aβ-treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2-CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Aβ treatment, supporting the view that ApoER2-CTF exerts a modulatory role on reelin expression.-Mata-Balaguer, T., Cuchillo-Ibañez, I., Calero, M., Ferrer, I., Sáez-Valero, J. Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 99%

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

et al. 2018

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“…Therefore, the fact that children with autism display a large increase in reelin monomers levels after denaturation suggests the existence of a higher proportion of reelin dimers/oligomers in the plasma of these children with regards to non-ASD children. Differences in reelin complexes have been reported in other neurological condition such as Alzheimer's disease (29,30). Remarkably, recent data indicate that commercial anti-reelin antibodies display different reactivity to monomeric or dimeric reelin protein (31), which highlights the relevance of an appropriate methodological design for reelin quantitative analyses.…”

Section: Discussionmentioning

confidence: 91%

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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“…Accordingly, insufficient Reelin signaling could contribute to the pathogenesis of neuropsychiatric disorders, such as epilepsy [17][18][19] , schizophrenia 6,16,20 , and autism 3,8,16 . Furthermore, recent studies showed that a decrease or insufficiency in Reelin signaling could aggravate Alzheimer's disease (AD) 13,[21][22][23][24][25][26] . Therefore, it is important to understand the molecular mechanisms by which Reelin is regulated.…”

Section: Introductionmentioning

confidence: 99%

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Okugawa

Ogino

Shigenobu

et al. 2020

Preprint

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Reelin is a secreted protein that plays versatile roles in neuronal development and function, and hypoactivity of Reelin is implicated in many neuropsychiatric disorders. The strength of Reelin signaling is regulated by proteolytic processing, but its importance in vivo is not yet fully understood. Here, we generated Reelin knock-in (PA-DV KI) mice in which the key cleavage site of Reelin was abolished by mutation. As expected, the cleavage of Reelin was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice. The amount of Dab1, whose degradation is induced by Reelin signaling, decreased in these tissues, indicating that the signaling strength of Reelin was augmented. The brains of PA-DV KI mice were largely structurally normal, but unexpectedly, the hippocampal layer was disturbed. This phenotype was ameliorated in hemizygote PA-DV KI mice, indicating that excess Reelin signaling is detrimental to hippocampal layer formation. The neuronal dendrites of PA-DV KI mice had more branches and were elongated compared to wild-type mice. These results present the first direct evidence of the physiological importance of Reelin cleavage and suggest that inhibition of Reelin cleavage would counteract neuropsychiatric disorders without causing severe systemic side effects.

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Reelin in Alzheimer’s Disease, Increased Levels but Impaired Signaling: When More is Less

Cited by 34 publications

References 143 publications

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

Elevated Plasma Reelin Levels in Children With Autism

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

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