Reelin Immunoreactivity in the Adult Primate Brain: Intracellular Localization in Projecting and Local Circuit Neurons of the Cerebral Cortex, Hippocampus and Subcortical Regions

Martínez‐Cerdeño, Verónica; Galazo, María J.; Cavada, Carmen; Clascá, Francisco

doi:10.1093/cercor/12.12.1298

Cited by 58 publications

(83 citation statements)

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“…The complex pattern of Reelin expression is consistent with evidence that this protein has multiple roles in brain development and adult brain function (7)(8)(9). In the adult mammalian brain, Reelin has been proposed to influence synaptogenesis and neural plasticity and to favor memory formation (8)(9)(10)(11)(12).…”

supporting

confidence: 78%

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

Botella-López

Burgaya

Gavı́n

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

188

153

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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.eelin is an extracellular 420-kDa glycoprotein that binds to the transmembrane receptors apolipoprotein receptor 2 and very-low-density lipoprotein receptor (1, 2), which transduce the Reelin signal through the intracellular adapter disabled-1 (3-5). Reelin signaling triggers a disabled-1-dependent signaling cascade involving several kinases, which ultimately controls proper neuronal migration and positioning during CNS development (for review see ref. 6).The complex pattern of Reelin expression is consistent with evidence that this protein has multiple roles in brain development and adult brain function (7-9). In the adult mammalian brain, Reelin has been proposed to influence synaptogenesis and neural plasticity and to favor memory formation (8)(9)(10)(11)(12). Reelin is also expressed in peripheral tissues, including the liver, and is detected in blood (10, 13). However, whether brain and other tissues contribute to the pool of Reelin in blood remains to be elucidated. In this context, we recently reported the presence of detectable levels of Reelin in adult cerebrospinal fluid (CSF) (14).Furthermore, the involvement of the Reelin signaling pathway in neurodegeneration has also been proposed (1,6,9,(15)(16)(17). First, Reelin binds to apolipoprotein E (ApoE) receptors, and some ApoE gene polymorphisms are considered risk factors for Alzheimer's disease (AD). Moreover, the lack of Reelin is associated with increased phosphorylation of Tau (1, 2, 18), whose hyperphosphorylation leads to intracel...

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supporting

confidence: 78%

“…In the adult mammalian brain, Reelin has been proposed to influence synaptogenesis and neural plasticity and to favor memory formation (8)(9)(10)(11)(12). Reelin is also expressed in peripheral tissues, including the liver, and is detected in blood (10, 13).…”

mentioning

confidence: 99%

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

Botella-López

Burgaya

Gavı́n

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

188

153

View full text Add to dashboard Cite

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“…1C), where it modulates spine dynamics and synaptic plasticity, as well as suppresses Tau hyperphosphorylation (Herz and Chen, 2006, Forster et al, 2010, Knuesel, 2010. As documented previously (Alcantara et al, 1998, Martinez-Cerdeno et al, 2002, Ramos-Moreno et al, 2006, Reelin is expressed by granule, mitral and tufted cells of the olfactory bulb. Its immunoreactivity can be further detected along the long projections of the latter two principal cell types: the lateral olfactory tract and olfactory tubercle, as well as in the neuropil of their projection areas: anterior olfactory nucleus, amygdala, piriform and entorhinal cortex.…”

Section: Reelin Expression Within Olfactory-limbic Pathwaysmentioning

confidence: 88%

“…Interestingly in primates, but not in rodents, Reelin continues to be expressed in the isocortical layers I and II and by interneurons throughout the neocortex (Alcantara et al, 1998, Martinez-Cerdeno et al, 2002, Ramos-Moreno et al, 2006 where the pathology appears only in advanced stages of the AD (Braak and Braak, 1991).…”

Section: Reelin Expression Within Olfactory-limbic Pathwaysmentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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“…Reelin expression starts in the developing brain and continues in GABAergic neurons of the cortex and the hippocampus and in glutamatergic granule cells of the cerebellum in adult rodents (Alcantara et al, 1998;Pesold et al, 1998;Ramos-Moreno et al, 2006), non-human primates (Martinez-Cerdeno et al, 2002) and adult humans (Abraham and Meyer, 2003). Besides its well defined role in brain development, Reelin was more recently studied in the context of adult mammalian brain, where its function remains quite obscure.…”

Section: Introductionmentioning

confidence: 99%