Reelin expression and glycosylation patterns are altered in Alzheimer's disease

Complutense University of Madrid, Madrid, Madrid, Spain
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2006; 103(14):5573-8. DOI: 10.1073/pnas.0601279103
Source: PubMed


Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.

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Available from: Javier Saez-Valero
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    • "One such molecule, reelin, is an extracellular glycoprotein that plays a major role in neuronal migration, brain lamination and positioning during the early development (Alcantara et al., 1998), plasticity (D'Arcangelo et al., 1995), adult learning (Weeber et al., 2002), working memory (Wedenoja et al., 2008), and executive function (Baune et al., 2010). It is secreted by Cajal- Retzius cells (Ogawa et al., 1995) and has become a key focus point of study for various mental health-associated illness and conditions such as Alzheimer's (Botella-Lopez et al., 2006), autism (Serajee, Zhong, & Mahbubul Huq, 2006), bipolar disorder, depression and schizophrenia (Fatemi, Earle, & McMenomy, 2000; Fatemi, Stary, Earle, Araghi-Niknam, & Egan, 2005; Folsom & Fatemi, 2013). Reelin (RELN) is located on chromosome 7q22 (DeSilva et al., 1997) and various RELN SNPs, DNA methylation sites and GGC polymorphic repeats (Figure 1) have been shown to regulate reelin mRNA expression and protein translational levels (Abdolmaleky et al., 2005; Persico, Levitt, & Pimenta, 2006; Tamura, Kunugi, Ohashi, & Hohjoh, 2007). "
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    ABSTRACT: Stress is clearly associated with the quality of life and many diseases, including mental disorders, with cortisol being a recognized biomarker for stress. Polymorphisms of the serotonin transporter gene (5-HTT), which results in long and short forms, have been reported to be associated with depression among major depressive disorder (MDD) patients. We have previously shown that 5-HTTLPR and waking cortisol do not predict depression in a general population sample, however, psychological resilience is a defence against depression. Reelin is an emerging biomarker for psychological resilience that plays an active role in neuronal migration. It is responsible for cytoarchitechtonic pattern formation in brain and modulates the migration of newly generated postmitotic neurons from the ventricular zone. In mice, overexpression of reelin in the hippocampus has anti-depressant activity by increasing neurogenesis and improving learning. A number of single nucleotide polymorphisms (SNPs), methylation of the promoter and coding region of the reelin (RELN) gene have been identified which affect the level of RELN mRNA and protein expression. Thus RELN is a potential candidate as a biomarker of psychological resilience and we have developed a rapid high-resolution melting (HRM) PCR analysis technique for the RELN SNPs and loci using gDNA isolated from buccal cells to test this hypothesis.
    Full-text · Article · Jun 2015
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    • "Increase in expression of the Reelin gene has been confirmed in two different AD cohorts [10,11], and has been associated with the specific vulnerability of neurons to AD [13]. We also have previously demonstrated that Aβ alters Reelin glycosylation, resulting in a glycosylation pattern similar to that of Reelin from cortex and cerebrospinal fluid (CSF) of AD patients [10,11]. The physiological consequences of alterations in Reelin expression are still unclear. "
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    ABSTRACT: Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer's disease that relevantly modulates tau phosphorylation. We have previously demonstrated that β-amyloid peptide (Aβ) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by Aβ will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by β-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3β kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3β activity, is up-regulated during defective reelin signaling. Binding of reelin to its receptor, mainly ApoER2 in the brain, relays the signal into the cell. We associate the impaired reelin signaling with inefficiency of reelin in forming active homodimers and decreased ability to bind efficiently to its receptor, ApoER2. More remarkably, reelin from Alzheimer cortex shows a tendency to form large complexes instead of homodimers, the active form for signaling. Our results suggest that reelin expression is altered by Aβ leading to impaired reelin signaling.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "To assess whether the immunohistochemical findings correlate with the levels of Reelin and its physiologically produced proteolytic fragments in the CSF, previously investigated in AD and ND subjects but yielding conflicting results [36,50,51], we performed a biochemical analysis of the CSF samples collected for each individual of our study. Besides the well-described immunoreactive bands representing full-length Reelin, the NR6 (310 kDa) and NR2 (180 kDa) fragments, we detected an additional band running at around 60 kDa. "
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    ABSTRACT: Reelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions. Reductions in Reelin levels have been suggested to contribute to Alzheimer's disease (AD) pathophysiology. We have previously reported an age-related reduction in Reelin levels and its accumulation in neuritic varicosities along the olfactory-limbic tracts, which correlated with cognitive impairments in aged mice. Here, we aimed to investigate whether a similar Reelin-associated neuropathology is observed in the aged human hippocampus and whether it correlated with dementia status. Our immunohistochemical stainings revealed the presence of N- and C-terminus-containing Reelin fragments in corpora amylacea (CAm), aging-associated spherical deposits. The density of these deposits was increased in the molecular layer of the subiculum of AD compared to non-demented individuals. Despite the limitation of a small sample size, our evaluation of several neuronal and glial markers indicates that the presence of Reelin in CAm might be related to aging-associated impairments in neuronal transport leading to accumulation of organelles and protein metabolites in neuritic varicosities, as previously suggested by the findings and discussions in rodents and primates. Our results indicate that aging- and disease-associated changes in Reelin levels and proteolytic processing might play a role in the formation of CAm by altering cytoskeletal dynamics. However, its presence may also be an indicator of a degenerative state of neuritic compartments.
    Full-text · Article · Jun 2013
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