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

ABSTRACT: 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.

SUBMITTER: Botella-Lopez A

PROVIDER: S-EPMC1414634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The amyloid precursor protein (APP) is a transmembrane glycoprotein that undergoes alternative proteolytic processing. Its processing through the amyloidogenic pathway originates a large sAPP? ectodomain fragment and the ?-amyloid peptide, while non-amyloidogenic processing generates sAPP? and shorter non-fibrillar fragments. Hence, measuring sAPP? and sAPP? has been proposed as a means to identify imbalances between the amyloidogenic/non-amyloidogenic pathways in the brain of Alzheimer's disease (AD) patients. However, to date, no consistent changes in these proteolytic fragments have been identified in either the brain or cerebrospinal fluid of AD individuals. METHODS:In frontal cortex homogenates from AD patients (n?=?7) and non-demented controls (NDC; n?=?7), the expression of total APP mRNA and that of the APP isoforms generated by alternative splicing, APP695 and APP containing the Kunitz protease inhibitor (KPI), was analyzed by qRT-PCR using TaqMan and SYBR Green probes. The balance between the amyloidogenic/non-amyloidogenic pathways was examined in western blots estimating the sAPP? and sAPP? fragments and their membrane-tethered C-terminal fragments CTF? and CTF?. CHO-PS70 cells, stably over-expressing wild-type human APP, served to evaluate whether A?42 peptide treatment results in altered APP glycosylation. We determined the glycosylation pattern of sAPP? and sAPP? in brain extracts and CHO-PS70 culture media by lectin-binding assays. RESULTS:In the cortex of AD patients, we detected an increase in total APP mRNA relative to the controls, due to an increase in both the APP695 and APP-KPI variants. However, the sAPP? or sAPP? protein levels remained unchanged, as did those of CTF? and CTF?. We studied the glycosylation of the brain sAPP? and sAPP? using lectins and pan-specific antibodies to discriminate between the fragments originated from neuronal APP695 and glial/KPI variants. Lectin binding identified differences in the glycosylation of sAPP? species derived from the APP695 and APP-KPI variants, probably reflecting their distinct cellular origin. Moreover, the lectin-binding pattern differed in the sAPP? and sAPP? originated from all the variants. Finally, when the lectin-binding pattern was compared between AD and NDC groups, significant differences were evident in sAPP? glycosylation. Lectin binding of the soluble sAPP? and sAPP? from CHO-PS70 cells were also altered in cells treated with the A? peptide. CONCLUSION:Our analysis of the lectin binding to sAPP? and sAPP? suggests that glycosylation dictates the proteolytic pathway for APP processing. Differences between the demented and controls indicate that changes in glycosylation may influence the generation of the different APP fragments and, consequently, the pathological progression of AD.

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

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