Abstract
Reelin is an extracellular glycoprotein that modulates neuronal function and synaptic plasticity in the adult brain. Decreased levels of Reelin activity have been postulated as a key factor during neurodegeneration in Alzheimer’s disease (AD) and in aging. Thus, changes in levels of full-length Reelin and Reelin fragments have been revealed in cerebrospinal fluid (CSF) and in post-mortem brains samples of AD patients with respect to non-AD patients. However, conflicting studies have reported decreased or unchanged levels of full-length Reelin in AD patients compared to control (nND) cases in post-mortem brains and CSF samples. In addition, a compelling analysis of Reelin levels in neurodegenerative diseases other than AD is missing. In this study, we analyzed brain levels of RELN mRNA and Reelin protein in post-mortem frontal cortex samples from different sporadic AD stages, Parkinson’s disease with dementia (PDD), and Creutzfeldt-Jakob disease (sCJD), obtained from five different Biobanks. In addition, we measured Reelin protein levels in CSF samples of patients with mild cognitive impairment (MCI), dementia, or sCJD diagnosis and a group of neurologically healthy cases. The results indicate an increase in RELN mRNA in the frontal cortex of advanced stages of AD and in sCJD(I) compared to controls. This was not observed in PDD and early AD stages. However, Reelin protein levels in frontal cortex samples were unchanged between nND and advanced AD stages and PDD. Nevertheless, they decreased in the CSF of patients with dementia in comparison to those not suffering with dementia and patients with MCI. With respect to sCJD, there was a tendency to increase in brain samples in comparison to nND and to decrease in the CSF with respect to nND. In conclusion, Reelin levels in CSF cannot be considered as a diagnostic biomarker for AD or PDD. However, we feel that the CSF Reelin changes observed between MCI, patients with dementia, and sCJD might be helpful in generating a biomarker signature in prodromal studies of unidentified dementia and sCJD.
Highlights
The extracellular glycoprotein Reelin plays relevant roles during development, circuit maturation, and synapse maintenance of the central nervous system (CNS) [1,2,3]
Several reports support a protective role of Reelin in preventing cognitive decline in Alzheimer’s disease (AD) and tauopathy mouse models [36,37,38]
Overproduced Reelin under these conditions, leading to increased reactive oxygen species in treated cells, is unable to trigger Disabled-1 (Dab1)-mediated intracellular signaling in target neurons [15]
Summary
The extracellular glycoprotein Reelin plays relevant roles during development, circuit maturation, and synapse maintenance of the central nervous system (CNS) [1,2,3]. The full-length Reelin protein (≈420 kD) is cleaved by several extracellular proteases. (i) the N-t cleavage (between 1244 and 1245 aa), mediated by metalloproteinases, such as a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS) family, (ii) WC cleavage 3455 and 3456 aa) mediated by proprotein convertase family proteases, and (iii) C-t cleavage With some controversy [5,8,9,10], it seems that the N-t cleavage of Reelin is able to inactivate Reelin function by ADAMTS 3, at least during embryonic development [11]
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