Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

University of California, San Francisco, San Francisco, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2007; 27(11):2727-33. DOI: 10.1523/JNEUROSCI.3758-06.2007
Source: PubMed


Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD). Cell surface receptors for Reelin, including integrins and very-low-density lipoprotein receptor/apolipoprotein E2 receptor, may be targets of amyloid-beta (Abeta) peptides presumed to play key roles in the pathogenesis of AD. Reelin also regulates the extent of tau phosphorylation. Finally, increased amounts of Reelin fragments have been found in CSF from AD patients, suggesting altered processing of Reelin. We therefore hypothesized that Reelin levels might be altered in the brains of human amyloid precursor protein (hAPP) transgenic mice, particularly in brain regions vulnerable to AD such as hippocampus and entorhinal cortex. Compared with nontransgenic controls, hAPP mice had significantly fewer Reelin-expressing pyramidal cells in the entorhinal cortex, the major population of glutamatergic neurons expressing Reelin in the brain. Western blot analysis of the hippocampus, which receives projections from the entorhinal cortex, revealed significant reductions in Reelin levels. In contrast, the number of Reelin-expressing GABAergic interneurons was not altered in either the entorhinal cortex or the hippocampus. Thus, neuronal expression of hAPP/Abeta is sufficient to reduce Reelin expression in a specific population of entorhinal cortical pyramidal neurons in vivo. Underscoring the relevance of these findings, we found qualitatively similar reductions of Reelin-expressing pyramidal neurons in the entorhinal cortex of AD brains. We conclude that alterations in Reelin processing or signaling may be involved in AD-related neuronal dysfunction.

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    • "Syndecan2 is likely co-deposited with A␤ 40 [34] and is involved in the formation of cerebral amyloid angiopathy [35]. Reelin, which was reduced here in AD CSF is apparently decreased in brain of A␤PP-overexpressing mice [36] [37], and is thought to be neuroprotective, perhaps by delaying fibril formation through a physical interaction with soluble A␤ 42 species [38]. "
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    ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
    Full-text · Article · Oct 2014 · Journal of Alzheimer's disease: JAD
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    • "We found evidence of increased excitability, supporting previous suggestions that epileptiform activity is a characteristic of mouse models of AD where familial mutations of hAPP are overexpressed (Noebels, 2011; Palop and Mucke, 2009). Furthermore, the data support the idea that defects that are relevant to AD occur in the EC (Chin et al., 2007; Francis et al., 2012). They suggest that impairments occur very early in life but they may require assays other than those that are commonly used to be detected. "
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    ABSTRACT: The entorhinal cortex (EC) is one of the first brain areas to display neuropathology in Alzheimer's disease. A mouse model which simulates amyloid-β (Aβ) neuropathology, the Tg2576 mouse, was used to address these early changes. Here, we show EC abnormalities occur in 2- to 4-month-old Tg2576 mice, an age before Aβ deposition and where previous studies suggest that there are few behavioral impairments. First we show, using a sandwich enzyme-linked immunosorbent assay, that soluble human Aβ40 and Aβ42 are detectable in the EC of 2-month-old Tg2576 mice before Aβ deposition. We then demonstrate that 2- to 4-month-old Tg2576 mice are impaired at object placement, an EC-dependent cognitive task. Next, we show that defects in neuronal nuclear antigen expression and myelin uptake occur in the superficial layers of the EC in 2- to 4-month-old Tg2576 mice. In slices from Tg2576 mice that contained the EC, there were repetitive field potentials evoked by a single stimulus to the underlying white matter, and a greater response to reduced extracellular magnesium ([Mg(2+)]o), suggesting increased excitability. However, deep layer neurons in Tg2576 mice had longer latencies to antidromic activation than wild type mice. The results show changes in the EC at early ages and suggest that altered excitability occurs before extensive plaque pathology.
    Full-text · Article · Jul 2014 · Neurobiology of Aging
    • "Reelin is known to modulate synaptic plasticity by enhancing the induction and maintenance of long-term potentiation[922]. In addition, reelin has recently been implicated in some neurological diseases, such as temporal lobe epilepsy and Alzheimer's disease[232425]. However, the relationship between Cajal-Retzius cells and Alzheimer's disease is unknown. "
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    ABSTRACT: Cajal-Retzius cells are reelin-secreting neurons in the marginal zone of the neocortex and hippocampus. The aim of this study was to investigate Cajal-Retzius cells in Alzheimer's disease pathology. Results revealed that the number of Cajal-Retzius cells markedly reduced with age in both wild type and in mice over-expressing the Swedish double mutant form of amyloid precursor protein 695 (transgenic (Tg) 2576 mice). Numerous reelin-positive neurons were positive for activated caspase 3 in Tg2576 mice, suggesting that Cajal-Retzius neuronal loss occurred via apoptosis in this Alzheimer's disease model. Compared with wild type, the number of Cajal-Retzius cells was significantly lower in Tg2576 mice. Western blot analysis confirmed that reelin levels were markedly lower in Tg2576 mice than in wild-type mice. The decline in Cajal-Retzius cells in Tg2576 mice was found to occur concomitantly with the onset of Alzheimer's disease amyloid pathology and related behavioral deficits. Overall, these data indicated that Cajal-Retzius cell loss occurred with the onset and development of Alzheimer's disease.
    No preview · Article · Feb 2014 · Neural Regeneration Research
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