Reversing EphB2 depletion rescues cognitive functions in Alzheimer model

Cissé, Moustapha Alfa; Halabisky, Brian; Harris, Julie A.; Devidze, Nino; Dubal, Dena B.; Sun, Binggui; Orr, Anna G.; Lotz, Gregor P.; Kim, Daniel H.; Hamto, Patricia; Ho, Kaitlyn; Yu, Gui-Qiu; Mucke, Lennart

doi:10.1038/nature09635

Cited by 380 publications

(428 citation statements)

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“…We focused our analysis on the relationships between the age‐upregulated miRNAs and the expression of genes in the Eph/ephrin pathway as Eph signaling regulates synaptic plasticity and loss of EphB2 has been linked to age‐related cognitive dysfunction (Klein, 2008; Cissé et al ., 2011). As many of the single components in the Eph/ephrin signaling pathway have multiple isoforms, we examined the expression of each gene by qRT–PCR.…”

Section: Resultsmentioning

confidence: 99%

“…EphB2 is known to control the surface expression of the NMDAR NR1 subunit in hippocampal neurons (Cissé et al ., 2011; Nolt et al ., 2011), expression necessary for the induction of a robust form of long‐term hippocampal potentiation (Klein, 2008). In addition, EphB2 controlled the surface expression of NR1 in an AD mouse model, which could account for the reduced synaptic plasticity and learning deficits in these mice (Cissé et al ., 2011).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, EphB2 controlled the surface expression of NR1 in an AD mouse model, which could account for the reduced synaptic plasticity and learning deficits in these mice (Cissé et al ., 2011). Collectively, these results suggest that miR‐204 downregulates the surface expression of the NR1 subunit in hippocampal neurons through EphB2.…”

Section: Resultsmentioning

confidence: 99%

“…The decrease in NR1 surface expression induced by miR‐204 transfection was likely due, at least in part, to the repression of EphB2 as miR‐204 represses EphB2, and EphB2 controls the surface expression of NR1 (Cissé et al ., 2011; Nolt et al ., 2011). However, EphB2 is not known to regulate the total cellular expression of NR1.…”

Section: Resultsmentioning

confidence: 99%

“…Alzheimer disease (AD), one of the most devastating age‐related neurological diseases, involves functional impairment of the hippocampus, and older age is the greatest risk factor for idiopathic AD. It was recently shown that the transmembrane receptor tyrosine kinase EphB2 is depleted in the hippocampus of an AD mouse model and that reversing this depletion can rescue cognitive function (Cissé et al ., 2011). Binding of EphB2 to its physiological ligand ephrin initiates signaling pathways critical for neuroplastic processes such as axon guidance, angiogenesis, and long‐term potentiation, a form of associative synaptic plasticity observed at hippocampal synapses (Klein, 2008).…”

Section: Introductionmentioning

confidence: 99%

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miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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SummaryHippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age‐associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR‐204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR‐204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR‐204 also decreased the total expression of NR1. miR‐204 induces senescence‐like phenotype in fully matured neurons as evidenced by an increase in p16‐positive cells. We suggest that aging is accompanied by the upregulation of miR‐204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age‐associated decline in hippocampal synaptic plasticity and the related cognitive functions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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Identification of approved drugs that inhibit the binding of amyloid β oligomers to ephrin type‐B receptor 2

et al. 2016

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Ephrin type‐B receptor 2 (EphB2) is a member of the receptor tyrosine kinase family and plays an important role in learning and memory functions. In patients with Alzheimer's disease ( AD ) and in mouse models of AD , a reduction in the hippocampal EphB2 level is observed. It was recently reported that normalization of the EphB2 level in the dentate gyrus rescues memory function in a mouse model of AD , suggesting that drugs that restore EphB2 levels may be beneficial in the treatment of AD . Amyloid β (Aβ) oligomers, which are believed to be key molecules involved in the pathogenesis of AD , induce EphB2 degradation through their direct binding to EphB2. Thus, compounds that inhibit the binding of Aβ oligomers to EphB2 may be beneficial. Here, we screened for such compounds from drugs already approved for clinical use in humans. Utilizing a cell‐free screening assay, we determined that dihydroergotamine mesilate, bromocriptine mesilate, cepharanthine, and levonorgestrel inhibited the binding of Aβ oligomers to EphB2 but not to cellular prion protein, another endogenous receptor for Aβ oligomers. Additionally, these four compounds did not affect the binding between EphB2 and ephrinB2, an endogenous ligand for EphB2, suggesting that the compounds selectively inhibited the binding of Aβ oligomers to EphB2. This is the first identification of compounds that selectively inhibit the binding of Aβ oligomers to EphB2. These results suggest that these four compounds may be safe and effective drugs for treatment of AD .

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Amyloid‐dependent and amyloid‐independent effects of Tau in individuals without dementia

Therriault

Pascoal

Sefranek

et al. 2021

Ann Clin Transl Neurol

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Objective To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau‐PET and clinical function were dependent on local amyloid‐PET (FWE corrected at p < 0.001). Interpretation In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid‐β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid‐β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau’s relationship with cognitive dysfunction was dependent on local amyloid‐β concentrations. Our results provide evidence that amyloid‐β in Alzheimer’s disease influences cognition by potentiating the deleterious effects of tau pathology.

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Reversing EphB2 depletion rescues cognitive functions in Alzheimer model

Cited by 380 publications

References 50 publications

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

Identification of approved drugs that inhibit the binding of amyloid β oligomers to ephrin type‐B receptor 2

Amyloid‐dependent and amyloid‐independent effects of Tau in individuals without dementia

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