Cognitive Decline Is Associated with Reduced Reelin Expression in the Entorhinal Cortex of Aged Rats

Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
Cerebral Cortex (Impact Factor: 8.67). 02/2011; 21(2):392-400. DOI: 10.1093/cercor/bhq106
Source: PubMed


Brain regions and neural circuits differ in their vulnerability to changes that occur during aging and in age-related neurodegenerative diseases. Among the areas that comprise the medial temporal lobe memory system, the layer II neurons of the entorhinal cortex, which form the perforant path input to the hippocampal formation, exhibit early alterations over the course of aging Reelin, a glycoprotein implicated in synaptic plasticity, is expressed by entorhinal cortical layer II neurons. Here, we report that an age-related reduction in reelin expression in the entorhinal cortex is associated with cognitive decline. Using immunohistochemistry and in situ hybridization, we observed decreases in the number of Reelin-immunoreactive cells and reelin messenger RNA expression in the lateral entorhinal cortex of aged rats that are cognitively impaired relative to young adults and aged rats with preserved cognitive abilities. The lateral entorhinal cortex of aged rats with cognitive impairment also exhibited changes in other molecular markers, including increased accumulation of phosphorylated tau and decreased synaptophysin immunoreactivity. Taken together, these findings suggest that reduced reelin expression, emanating from layer II entorhinal neurons, may contribute to network dysfunction that occurs during memory loss in aging.

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    • "In the context of aging, altered transcriptional regulation of genes that promote or are necessary for synaptic plasticity is associated with memory impairment in aged rodents (Blalock et al. 2003; Rowe et al. 2007; Haberman et al. 2011). Affected genes implicated in plasticity notably include the immediate-early genes HomerI1a, and Arc (activity regulated cytoskeleton-associated protein ), which are necessary for learning and memory (Penner et al. 2011), as well as zif268, bdnf (brain-derived neurotrophic factor ) (Hattiangady et al. 2005), and reelin (Stranahan et al. 2011). Data derived from a rodent model of neurocognitive aging in which old Long-Evans rats show individual variability in cognitive outcome highlight the marked changes in hippocampal gene transcription that occur in association with age-related memory impairment, thereby distinguishing neurobiological signatures that are specifically associated with age-related memory decline from changes coupled with chronological age, unrelated to cognitive outcome. "
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    ABSTRACT: Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review neuroepigenetic research as it relates to cognitive aging, focusing specifically on memory function mediated by the hippocampal system. Recent work that differentiates epigenetic contributions to chronological aging from influences on mindspan, or the preservation of normal cognitive abilities across the lifespan, is also highlighted. Together, current evidence indicates that while age-related memory impairment is associated with dysfunction in the coordinated regulation of chromatin modification, animal models that show individual differences in cognitive outcome underscore the enormous mechanistic complexity that surrounds epigenetic dynamics in the aged hippocampus.
    Learning & memory (Cold Spring Harbor, N.Y.) 10/2014; 21(10):569-574. DOI:10.1101/lm.033506.113 · 3.66 Impact Factor
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    • "The LEC appeared to be affected in aging more than the MEC, because there was reduced synaptophysin, decreased reelin and increased phosphorylated tau in LEC neurons in layer II of aged animals, when the MEC did not appear to be altered (Stranahan et al., 2010). Notably, some animals lacked abnormalities; when animals were tested using the Morris water maze, those rats with impairments had layer II defects, but the others that performed normally had no detectable changes in the EC (Stranahan et al., 2010). Although correlative, the results suggested that neurons in layer II, especially in LEC, could play an important role in age-related cognitive impairment. "
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    ABSTRACT: A major problem in the field of neurodegeneration is the basis of selective vulnerability of subsets of neurons to disease. In aging, Alzheimer's disease (AD), and other disorders such as temporal lobe epilepsy, the superficial layers of the entorhinal cortex (EC) are an area of selective vulnerability. In AD, it has been suggested that the degeneration of these neurons may play a role in causing the disease because it occurs at an early stage. Therefore, it is important to define the distinctive characteristics of the EC that make this region particularly vulnerable. It has been shown that neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical to the maintenance of the cortical neurons in the adult brain, and specifically the EC. Here we review the circuitry, distinctive functions, and neurotrophin-dependence of the EC that are relevant to its vulnerability. We also suggest that a protein that is critical to the actions of BDNF, the ARMS/Kidins220 scaffold protein, plays an important role in neurotrophic support of the EC.
    Cognitive neuroscience 08/2013; 4(3-4). DOI:10.1080/17588928.2013.826184 · 2.65 Impact Factor
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    • "Recent experimental evidence further highlighted that Reelin maintains synaptic plasticity by competing with ApoE4 to prevent the latter from sequestering NMDA, AMPA, and ApoER2 receptors in intracellular compartments [27]. In line with the well described aging-associated synaptic impairments, Reelin expression has been shown to decline in aging rodents, correlating with hippocampus-dependent learning and memory performance [28,29]. Furthermore, Reelin accumulates within neuritic varicosities in both rodents and non-human primates [28,30], possibly related to the aging associated decrease in Reelin signaling and its protective modulation of cytoskeleton dynamics [10]. "
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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.
    06/2013; 1(1):27. DOI:10.1186/2051-5960-1-27
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