Abstract
Reelin is a neurodevelopmental protein important in adult synaptic plasticity and learning and memory. Recent evidence points to the importance for Reelin proteolysis in normal signaling and in cognitive function. Support for the dysfunction of Reelin proteolysis in neurodegeneration and cognitive dysfunction comes from postmortem analysis of Alzheimer’s diseases (AD) tissues including cerebral spinal fluid (CSF), showing that levels of Reelin fragments are altered in AD compared to control. Potential key proteases involved in Reelin proteolysis have recently been defined, identifying processes that could be altered in neurodegeneration. Introduction of full-length Reelin and its proteolytic fragments into several mouse models of neurodegeneration and neuropsychiatric disorders quickly promote learning and memory. These findings support a role for Reelin in learning and memory and suggest further understanding of these processes are important to harness the potential of this pathway in treating cognitive symptoms in neuropsychiatric and neurodegenerative diseases.
Highlights
Introduction of exogenousReelin into the brain can have surprisingly profound effects on synaptic plasticity and cognition
Once Reelin is secreted by GABAergic interneurons into the extracellular space it binds to the lipoprotein receptors, verylow-density lipoprotein receptor (VLDLR) and Apolipoprotein receptor 2 (ApoER2; D’Arcangelo et al, 1999; Weeber et al, 2002; Herz and Chen, 2006; Figure 1)
Reelin signaling may not be driven by the simple production and release of Reelin from interneurons, as with neuropeptides or small molecule transmitters, but it may be regulated by the directed proteolysis of sequestered, full length, extracellular Reelin
Summary
Reelin is an extracellular matrix protein important in brain development during embryogenesis (for detailed reviews, see Lambert de Rouvroit et al, 1999; Rice and Curran, 2001; Tissir and Goffinet, 2003). During development Reelin is expressed by Cajal–Retzius cells. Reelin Proteolysis and Neurodegeneration in the hippocampus and cortex and granule cells in the cerebellum (Ogawa et al, 1995; Del Río et al, 1997; Frotscher, 1998; Hirota et al, 2015). In the adult brain GABAergic interneurons in the cortex and hippocampus secrete Reelin (Alcantara et al, 1998; Pesold et al, 1998). Much of what we know about the Reelin signaling pathway in development comes from mouse models that have knock-down or overexpression of critical proteins in the pathway: Reelin, lipoprotein receptors, and Disabled-1 (Dab1; Howell et al, 1997b; Hiesberger et al, 1999; Trommsdorff et al, 1999; Beffert et al, 2002; Drakew et al, 2002; Weeber et al, 2002; Qiu et al, 2006a; Pujadas et al, 2010, 2014; Teixeira et al, 2011; Trotter et al, 2013; Lane-Donovan et al, 2015)
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