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  1. Article: Developing Biomarkers of Mild Traumatic Brain Injury: Promise and Progress of CNS-Derived Exosomes.

    Vaughn, Melonie N / Winston, Charisse N / Levin, Natalie / Rissman, Robert A / Risbrough, Victoria B

    Frontiers in neurology

    2022  Volume 12, Page(s) 698206

    Abstract: Mild traumatic brain injuries (mTBI) are common injuries across civilian and military populations. Although most individuals recover after mTBI, some individuals continue to show long-term symptoms as well as increased risk for neurodegenerative and ... ...

    Abstract Mild traumatic brain injuries (mTBI) are common injuries across civilian and military populations. Although most individuals recover after mTBI, some individuals continue to show long-term symptoms as well as increased risk for neurodegenerative and neuropsychiatric disorders. Currently, diagnosing TBI severity relies primarily on self-report and subjective symptoms, with limited tools for diagnosis or prognosis. Brain-derived exosomes, a form of extracellular vesicle, may offer a solution for interpreting injury states by aiding in diagnosis as well as outcome prediction with relatively low patient burden. Exosomes, which are released into circulation, contain both protein and RNA cargo that can be isolated and quantified, providing a molecular window into molecular status of the exosome source. Here we examined the current literature studying the utility of exosomes, in particular neuronal- and astrocyte-derived exosomes, to identify protein and miRNA biomarkers of injury severity, trajectory, and functional outcome. Current evidence supports the potential for these emerging new tools to capture an accessible molecular window into the brain as it responds to a traumatic injury, however a number of limitations must be addressed in future studies. Most current studies are relatively small and cross sectional; prospective, longitudinal studies across injury severity, and populations are needed to track exosome cargo changes after injury. Standardized exosome isolation as well as advancement in identifying/isolating exosomes from CNS-specific tissue sources will improve mechanistic understanding of cargo changes as well as reliability of findings. Exosomes are also just beginning to be used in model systems to understand functional effects of TBI-associated cargo such as toxicity. Finally linking exosome cargo changes to objective markers of neuronal pathology and cognitive changes will be critical in validating these tools to provide insights into injury and recovery states after TBI.
    Language English
    Publishing date 2022-02-10
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564214-5
    ISSN 1664-2295
    ISSN 1664-2295
    DOI 10.3389/fneur.2021.698206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Evaluation of blood-based, extracellular vesicles as biomarkers for aging-related TDP-43 pathology.

    Winston, Charisse N / Sukreet, Sonal / Lynch, Haley / Lee, Virginia M-Y / Wilcock, Donna M / Nelson, Peter T / Rissman, Robert A

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2022  Volume 14, Issue 1, Page(s) e12365

    Abstract: Introduction: Limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. To date, LATE-NC is difficult to diagnose antemortem using ... ...

    Abstract Introduction: Limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. To date, LATE-NC is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of extracellular vesicle (EVs) protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases.
    Methods: TDP-43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE (n = 22). Quantified TDP-43 concentrations were compared to the cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE-NC (n = 42).
    Results: TDP-43 was significantly elevated in plasma ADEVs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in EV-depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between EV TDP-43 levels with cognition-based variables, sex, and APOE carrier status.
    Discussion: Blood-based EVs, specifically measuring TDP-43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.
    Language English
    Publishing date 2022-12-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12365
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview.

    Badhwar, AmanPreet / Hirschberg, Yael / Tamayo, Natalia Valle / Iulita, M Florencia / Udeh-Momoh, Chinedu T / Matton, Anna / Tarawneh, Rawan M / Rissman, Robert A / Ledreux, Aurélie / Winston, Charisse N / Haqqani, Arsalan S

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Introduction: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV- ... ...

    Abstract Introduction: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols.
    Methods: NDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type- specificity; extracellular domains (ECD+); and presence in EV-databases.
    Results: 82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV- databases.
    Discussion: We identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers.
    Language English
    Publishing date 2023-10-02
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.02.560210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Complement protein levels in plasma astrocyte-derived exosomes are abnormal in conversion from mild cognitive impairment to Alzheimer's disease dementia.

    Winston, Charisse N / Goetzl, Edward J / Schwartz, Janice B / Elahi, Fanny M / Rissman, Robert A

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2019  Volume 11, Page(s) 61–66

    Abstract: Introduction: Levels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).: Methods: Participants (n = 20 per group) had ... ...

    Abstract Introduction: Levels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).
    Methods: Participants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs.
    Results: ADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS.
    Discussion: ADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.
    Language English
    Publishing date 2019-01-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1016/j.dadm.2018.11.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer's Disease.

    Winston, Charisse N / Langford, Oliver / Levin, Natalie / Raman, Rema / Yarasheski, Kevin / West, Tim / Abdel-Latif, Sara / Donohue, Michael / Nakamura, Akinori / Toba, Kenji / Masters, Colin L / Doecke, James / Sperling, Reisa A / Aisen, Paul S / Rissman, Robert A

    Journal of Alzheimer's disease : JAD

    2023  Volume 92, Issue 1, Page(s) 95–107

    Abstract: Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective ... ...

    Abstract Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials.
    Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial.
    Methods: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N.
    Results: Plasma Aβ42/Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ42/Aβ40 to predict amyloid PET positivity in A4 Study participants.
    Conclusion: Plasma Aβ42/Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.
    MeSH term(s) Humans ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Cross-Sectional Studies ; Amyloid ; Amyloidogenic Proteins ; Biomarkers ; Positron-Emission Tomography ; Peptide Fragments
    Chemical Substances Amyloid beta-Peptides ; Amyloid ; Amyloidogenic Proteins ; Biomarkers ; Peptide Fragments
    Language English
    Publishing date 2023-01-31
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-221118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Modulation of Amyloid-β and Tau in Alzheimer's Disease Plasma Neuronal-Derived Extracellular Vesicles by Cerebrolysin® and Donepezil.

    Alvarez, X Anton / Winston, Charisse N / Barlow, James W / Sarsoza, Floyd M / Alvarez, Irene / Aleixandre, Manuel / Linares, Carlos / García-Fantini, Manuel / Kastberger, Birgit / Winter, Stefan / Rissman, Robert A

    Journal of Alzheimer's disease : JAD

    2022  Volume 90, Issue 2, Page(s) 705–717

    Abstract: Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance.: Objective: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, ...

    Abstract Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance.
    Objective: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD.
    Methods: Plasma NDEV levels of Aβ42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points.
    Results: NDEV levels of Aβ42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05).
    Conclusion: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.
    MeSH term(s) Humans ; Alzheimer Disease/diagnosis ; Donepezil/therapeutic use ; Neurogranin ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/diagnosis ; Biomarkers ; Extracellular Vesicles/metabolism ; Peptide Fragments/metabolism
    Chemical Substances Donepezil (8SSC91326P) ; cerebrolysin (37KZM6S21G) ; Neurogranin (132654-77-4) ; tau Proteins ; Amyloid beta-Peptides ; Biomarkers ; Peptide Fragments
    Language English
    Publishing date 2022-10-10
    Publishing country Netherlands
    Document type Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-220575
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment.

    Winston, Charisse N / Goetzl, Edward J / Baker, Laura D / Vitiello, Michael V / Rissman, Robert A

    Journal of Alzheimer's disease : JAD

    2018  Volume 66, Issue 3, Page(s) 971–981

    Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be ... ...

    Abstract Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.
    MeSH term(s) Aged ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Cognitive Dysfunction/blood ; Cognitive Dysfunction/drug therapy ; Double-Blind Method ; Exosomes/drug effects ; Female ; Growth Hormone-Releasing Hormone/pharmacology ; Growth Hormone-Releasing Hormone/therapeutic use ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Peptide Fragments/blood ; Synaptophysin/blood ; Synaptotagmins/blood
    Chemical Substances Amyloid beta-Peptides ; Biomarkers ; Peptide Fragments ; Synaptophysin ; amyloid beta-protein (1-42) ; Synaptotagmins (134193-27-4) ; Growth Hormone-Releasing Hormone (9034-39-3)
    Language English
    Publishing date 2018-11-07
    Publishing country Netherlands
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-180302
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice.

    Sloley, Stephanie S / Main, Bevan S / Winston, Charisse N / Harvey, Alex C / Kaganovich, Alice / Korthas, Holly T / Caccavano, Adam P / Zapple, David N / Wu, Jian-Young / Partridge, John G / Cookson, Mark R / Vicini, Stefano / Burns, Mark P

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 2613

    Abstract: Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice ... ...

    Abstract Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.
    MeSH term(s) Amyloid beta-Peptides/metabolism ; Animals ; Behavior Rating Scale ; Brain Injuries, Traumatic/genetics ; Brain Injuries, Traumatic/metabolism ; Cognition/drug effects ; Cognitive Dysfunction/pathology ; Electrophysiology ; Gene Ontology ; Glutamic Acid/metabolism ; Memantine/administration & dosage ; Mice ; Microglia/metabolism ; Multigene Family ; Neuronal Plasticity/genetics ; Neurons/cytology ; Neurons/pathology ; Receptors, N-Methyl-D-Aspartate/metabolism ; Synapses/genetics ; Synapses/metabolism ; Synapses/pathology ; Transcriptome/genetics ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; Receptors, N-Methyl-D-Aspartate ; tau Proteins ; Glutamic Acid (3KX376GY7L) ; Memantine (W8O17SJF3T)
    Language English
    Publishing date 2021-05-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-22744-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons.

    Podvin, Sonia / Jones, Alexander / Liu, Qing / Aulston, Brent / Mosier, Charles / Ames, Janneca / Winston, Charisse / Lietz, Christopher B / Jiang, Zhenze / O'Donoghue, Anthony J / Ikezu, Tsuneya / Rissman, Robert A / Yuan, Shauna H / Hook, Vivian

    ACS omega

    2021  Volume 6, Issue 20, Page(s) 13033–13056

    Abstract: The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer's disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. ... ...

    Abstract The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer's disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. Notably, exosomes from human-induced pluripotent stem cell (iPSC) neurons expressing the AD familial A246E mutant form of presenilin 1 (mPS1) are capable of inducing tau deposits in the mouse brain after
    Language English
    Publishing date 2021-05-13
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.1c00660
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Reduced cortical excitatory synapse number in APOE4 mice is associated with increased calcineurin activity.

    Neustadtl, Aidan L / Winston, Charisse N / Parsadanian, Maia / Main, Bevan S / Villapol, Sonia / Burns, Mark P

    Neuroreport

    2017  Volume 28, Issue 10, Page(s) 618–624

    Abstract: Synaptic loss is a symptom of Alzheimer's disease (AD) that is associated with the onset of cognitive decline and the loss of executive function. The strongest genetic risk factor for AD is the APOE4 allele, which results in both a greater risk of ... ...

    Abstract Synaptic loss is a symptom of Alzheimer's disease (AD) that is associated with the onset of cognitive decline and the loss of executive function. The strongest genetic risk factor for AD is the APOE4 allele, which results in both a greater risk of developing AD as well as an earlier age of onset of AD. Dendritic spines, the anatomical substrate of the excitatory synapse, are reduced in the cortex of humanized APOE4 mice but the reason for this synaptic decline is unknown. Calcineurin, a calcium/calmodulin dependent phosphatase, is a mediator of dendritic spine retraction. We used humanized APOE mice to examine how APOE genotype altered calcineurin activity and found that APOE4 mice have 35% higher cortical calcineurin activity compared with APOE3 mice. This occurred in the absence of any increase in calcineurin protein levels or mRNA expression. The elevation in calcineurin was associated with 10% fewer dendritic spine number in layer II/III of the cortex. Treatment with the calcineurin inhibitor FK506 reduced calcineurin activity by 64% and resulted in normalization of dendritic spine numbers in APOE4 mice. In conclusion, we found that the APOE4 gene in mice was associated with elevated calcineurin activity and fewer dendritic spine numbers compared with APOE3 mice. Importantly, calcineurin in APOE4 remained sensitive to pharmacological inhibition and spine density can be rescued by treatment with FK506.
    MeSH term(s) Animals ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Calcineurin/metabolism ; Calcineurin Inhibitors/pharmacology ; Cerebral Cortex/drug effects ; Cerebral Cortex/enzymology ; Cerebral Cortex/pathology ; Dendritic Spines/drug effects ; Dendritic Spines/enzymology ; Dendritic Spines/pathology ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; RNA, Messenger/metabolism ; Random Allocation ; Synapses/drug effects ; Synapses/enzymology ; Synapses/pathology ; Tacrolimus/pharmacology
    Chemical Substances Apolipoprotein E3 ; Apolipoprotein E4 ; Calcineurin Inhibitors ; RNA, Messenger ; Calcineurin (EC 3.1.3.16) ; Tacrolimus (WM0HAQ4WNM)
    Language English
    Publishing date 2017-05-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 1049746-8
    ISSN 1473-558X ; 0959-4965
    ISSN (online) 1473-558X
    ISSN 0959-4965
    DOI 10.1097/WNR.0000000000000811
    Database MEDical Literature Analysis and Retrieval System OnLINE

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