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  • 1
    Online Resource
    Online Resource
    An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice
    American Association for the Advancement of Science (AAAS) ; 2014
    In:  Science Translational Medicine Vol. 6, No. 236 ( 2014-05-14)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 6, No. 236 ( 2014-05-14)
    Abstract: Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.3008169
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    Bidirectional Relationship between Functional Connectivity and Amyloid-β Deposition in Mouse Brain
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 13 ( 2012-03-28), p. 4334-4340
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 13 ( 2012-03-28), p. 4334-4340
    Abstract: Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer's disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice before Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5845-11.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Reply to comment on “An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice”
    American Association for the Advancement of Science (AAAS) ; 2014
    In:  Science Translational Medicine Vol. 6, No. 268 ( 2014-12-24)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 6, No. 268 ( 2014-12-24)
    Abstract: Possible reasons for why a new study could not replicate our finding that the serotonin reuptake inhibitor citalopram decreased amyloid β concentrations in the cerebrospinal fluid of healthy volunteers.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.3010609
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 11 ( 2014-03-12), p. 3826-3840
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 11 ( 2014-03-12), p. 3826-3840
    Abstract: Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5171-13.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
    detail.hit.zdb_id: 1475274-8
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  • 5
    Online Resource
    Online Resource
    ApoE mimetic peptide decreases Aβ production in vitro and in vivo
    Springer Science and Business Media LLC ; 2010
    In:  Molecular Neurodegeneration Vol. 5, No. 1 ( 2010-12)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2010-12)
    Abstract: Apolipoprotein E (apoE) is postulated to affect brain Aβ levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Aβ degradation, and Aβ clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo . Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Aβ production. Results We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Aβ levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer 〉 dimer 〉 monomer). We previously showed that the apoE dimer increased APP CTF in vivo ; to determine whether the dimer also affected secreted APP or Aβ levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPα and decreased Aβ levels at 24 hrs after treatment, suggesting that the apoE dimer may increase α-secretase cleavage. Conclusions These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPα and decreased Aβ levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Aβ production both in vitro and in vivo .
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/1750-1326-5-16
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2244557-2
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  • 6
    Online Resource
    Online Resource
    Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 36 ( 2011-09-06), p. 14968-14973
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 36 ( 2011-09-06), p. 14968-14973
    Abstract: Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1107411108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
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    Online Resource
    Response to Comments on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models”
    American Association for the Advancement of Science (AAAS) ; 2013
    In:  Science Vol. 340, No. 6135 ( 2013-05-24), p. 924-924
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 340, No. 6135 ( 2013-05-24), p. 924-924
    Abstract: The data reported in the Technical Comments by Fitz et al ., Price et al ., Tesseur et al ., and Veeraraghavalu et al . replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble β-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer’s disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1234114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 8
    Online Resource
    Online Resource
    Neuronal activity regulates extracellular tau in vivo
    Rockefeller University Press ; 2014
    In:  The Journal of Cell Biology Vol. 204, No. 5 ( 2014-03-03), p. 2045OIA31-
    Details
    In: The Journal of Cell Biology, Rockefeller University Press, Vol. 204, No. 5 ( 2014-03-03), p. 2045OIA31-
    Type of Medium: Online Resource
    ISSN: 0021-9525 , 1540-8140
    URL: Article
    DOI: 10.1083/jcb.2045OIA31
    RVK:
    WA 15000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2014
    detail.hit.zdb_id: 1421310-2
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
    Springer Science and Business Media LLC ; 2013
    In:  Molecular Neurodegeneration Vol. 8, No. 1 ( 2013-12)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2013-12)
    Abstract: The APOE4 allele variant is the strongest known genetic risk factor for developing late-onset Alzheimer’s disease. The link between apolipoprotein E (apoE) and Alzheimer’s disease is likely due in large part to the impact of apoE on the metabolism of amyloid β (Aβ) within the brain. Manipulation of apoE levels and lipidation within the brain has been proposed as a therapeutic target for the treatment of Alzheimer’s disease. However, we know little about the dynamic regulation of apoE levels and lipidation within the central nervous system. We have developed an assay to measure apoE levels in the brain interstitial fluid of awake and freely moving mice using large molecular weight cut-off microdialysis probes. Results We were able to recover apoE using microdialysis from human cerebrospinal fluid (CSF) in vitro and mouse brain parenchyma in vivo . Microdialysis probes were inserted into the hippocampus of wild-type mice and interstitial fluid was collected for 36 hours. Levels of apoE within the microdialysis samples were determined by ELISA. The levels of apoE were found to be relatively stable over 36 hours. No apoE was detected in microdialysis samples from apoE KO mice. Administration of the RXR agonist bexarotene increased ISF apoE levels while ISF Aβ levels were decreased. Extrapolation to zero-flow analysis allowed us to determine the absolute recoverable concentration of apoE3 in the brain ISF of apoE3 KI mice. Furthermore, analysis of microdialysis samples by non-denaturing gel electrophoresis determined lipidated apoE particles in microdialysis samples were consistent in size with apoE particles from CSF. Finally, we found that the concentration of apoE in the brain ISF was dependent upon apoE isoform in human apoE KI mice, following the pattern apoE2 〉 apoE3 〉 apoE4. Conclusions We are able to collect lipidated apoE from the brain of awake and freely moving mice and monitor apoE levels over the course of several hours from a single mouse. Our technique enables assessment of brain apoE dynamics under physiological and pathophysiological conditions and in response to therapeutic interventions designed to affect apoE levels and lipidation within the brain.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/1750-1326-8-13
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 2244557-2
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  • 10
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    Online Resource
    Neuronal Clearance of Amyloid-β by Endocytic Receptor LRP1
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 49 ( 2013-12-04), p. 19276-19283
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 49 ( 2013-12-04), p. 19276-19283
    Abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-β (Aβ) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While Aβ production is accelerated in familial AD, increasing evidence indicates that impaired clearance of Aβ is responsible for late-onset AD. Because Aβ is mainly generated in neurons, these cells are predicted to have the highest risk of encountering Aβ among all cell types in the brain. However, it is still unclear whether they are also involved in Aβ clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain Aβ clearance. LRP1 is known to be an endocytic receptor for multiple ligands including Aβ. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain Aβ levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting Aβ production. In vivo microdialysis studies demonstrated that Aβ clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major Aβ degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed Aβ clearance is likely due to the suppression of LRP1-mediated neuronal Aβ uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of Aβ and indicate that neurons not only produce but also clear Aβ.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3487-13.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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