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  • 1
    Online Resource
    Online Resource
    ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 47 ( 2019-11-19), p. 23790-23796
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 47 ( 2019-11-19), p. 23790-23796
    Abstract: Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1908529116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
    Springer Science and Business Media LLC ; 2015
    In:  Nature Neuroscience Vol. 18, No. 7 ( 2015-07), p. 978-987
    Details
    In: Nature Neuroscience, Springer Science and Business Media LLC, Vol. 18, No. 7 ( 2015-07), p. 978-987
    Type of Medium: Online Resource
    ISSN: 1097-6256 , 1546-1726
    URL: Article
    DOI: 10.1038/nn.4025
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 1494955-6
    SSG: 12
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  • 3
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    LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 46 ( 2012-11-14), p. 16458-16465
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 46 ( 2012-11-14), p. 16458-16465
    Abstract: Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer's disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood–brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing Aβ out of the brain across the BBB; however, whether this represents a significant pathway for brain Aβ clearance remains controversial. Here, we demonstrate that Aβ can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous Aβ were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion of Lrp1 in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain Aβ accumulation and exacerbated Aβ deposition as amyloid plaques and CAA without affecting Aβ production. Our results demonstrate that LRP1 is a major Aβ clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Aβ accumulation. These studies establish critical functions of the cerebrovasculature system in Aβ metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3987-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
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  • 4
    Online Resource
    Online Resource
    Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression
    Oxford University Press (OUP) ; 2019
    In:  Brain Vol. 142, No. 4 ( 2019-04-01), p. 1077-1092
    Details
    In: Brain, Oxford University Press (OUP), Vol. 142, No. 4 ( 2019-04-01), p. 1077-1092
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awz011
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474117-9
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  • 5
    Online Resource
    Online Resource
    Prostaglandin D 2 -Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 16 ( 2006-04-19), p. 4383-4393
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 16 ( 2006-04-19), p. 4383-4393
    Abstract: Prostaglandin (PG) D 2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD 2 involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher , a model of human Krabbe’s disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP 1 receptor for PGD 2 in the brain of these mice. Cultured microglia actively produced PGD 2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD 2 receptor, DP 1 and DP 2 , and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD 2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD 2 /DP signaling pathway using HPGDS- or DP 1 -null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1 H -tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS-null and HQL-79-treated twitcher mice. These results suggest that PGD 2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4531-05.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 6
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    Online Resource
    Familial Frontotemporal Dementia-Associated Presenilin-1 c.548G〉T Mutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 15 ( 2012-04-11), p. 5085-5096
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 15 ( 2012-04-11), p. 5085-5096
    Abstract: Mutations in the presenilin-1 ( PSEN1 ) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G 〉 T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G 〉 T mutation on presenilin-1 (PS1) function in vivo , we introduced this mutation into the genomic Psen1 locus. The resulting c.548G 〉 T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo γ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G 〉 T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G 〉 V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G 〉 T KI/KI ;Psen2 −/− mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G 〉 T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0317-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
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  • 7
    Online Resource
    Online Resource
    Heparan Sulphate Proteoglycan and the Low-Density Lipoprotein Receptor-Related Protein 1 Constitute Major Pathways for Neuronal Amyloid-β Uptake
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 5 ( 2011-02-02), p. 1644-1651
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 5 ( 2011-02-02), p. 1644-1651
    Abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-β (Aβ) peptides in the brain are central to its pathogenesis. In healthy brains, Aβ is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of Aβ is one of the major pathways for its clearance in the brain. Increasing evidence has demonstrated significant roles for the low-density lipoprotein receptor-related protein 1 (LRP1) in the metabolism of Aβ in neurons, glia cells, and along the brain vasculatures. Heparan sulfate proteoglycan (HSPG) has also been implicated in several pathogenic features of AD, including its colocalization with amyloid plaques. Here, we demonstrate that HSPG and LRP1 cooperatively mediate cellular Aβ uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses Aβ uptake, whereas overexpression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular Aβ uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of Aβ. We further showed that HSPG is more important for the binding of Aβ to the cell surface than LRP1. The critical roles of HSPG in cellular Aβ binding and uptake were confirmed in Chinese hamster ovary cells genetically deficient in HSPG. We also showed that heparin and a neutralizing antibody to LRP1 suppressed Aβ uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular Aβ uptake and define a major pathway through which Aβ gains entry to neuronal cells.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5491-10.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Online Resource
    Prostaglandin D 2 Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 16 ( 2007-04-18), p. 4303-4312
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 16 ( 2007-04-18), p. 4303-4312
    Abstract: Prostaglandin D 2 (PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP 1 or DP 2 receptors. We investigated the role of PGD 2 in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD 2 production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed in L-PGDS or DP 2 knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased in HPGDS–L-PGDS double knock-out or DP 1 knock-out mice. The PGD 2 level in L-PGDS , HPGDS , and HPGDS–L-PGDS knock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD 2 production. DP 1 receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation in HPGDS–L-PGDS knock-out mice. Endothelial cells were severely damaged in HPGDS–L-PGDS and DP 1 knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD 2 protected the neonatal brain from hypoxic-ischemic injury mainly via DP 1 receptors by preventing endothelial cell degeneration.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0321-07.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
    detail.hit.zdb_id: 1475274-8
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  • 9
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    Online Resource
    Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 15 ( 2007-04-10), p. 6412-6417
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 15 ( 2007-04-10), p. 6412-6417
    Abstract: The conformational change in amyloid β (Aβ) peptide from its monomeric form to aggregates is crucial in the pathogenesis of Alzheimer's disease (AD). In the healthy brain, some unidentified chaperones appear to prevent the aggregation of Aβ. Here we reported that lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace, the most abundant cerebrospinal fluid (CSF) protein produced in the brain, was localized in amyloid plaques in both AD patients and AD-model Tg2576 mice. Surface plasmon resonance analysis revealed that L-PGDS/β-trace tightly bound to Aβ monomers and fibrils with high affinity ( K D = 18–50 nM) and that L-PGDS/β-trace recognized residues 25–28 in Aβ, which is the key region for its conformational change to a β-sheet structure. The results of a thioflavin T fluorescence assay to monitor Aβ aggregation disclosed that L-PGDS/β-trace inhibited the spontaneous aggregation of Aβ (1–40) and Aβ (1–42) within its physiological range (1–5 μM) in CSF. L-PGDS/β-trace also prevented the seed-dependent aggregation of 50 μM Aβ with K i of 0.75 μM. Moreover, the inhibitory activity toward Aβ (1–40) aggregation in human CSF was decreased by 60% when L-PGDS/β-trace was removed from the CSF by immunoaffinity chromatography. The deposition of Aβ after intraventricular infusion of Aβ (1–42) was 3.5-fold higher in L-PGDS-deficient mice and reduced to 23% in L-PGDS-overexpressing mice as compared with their wild-type levels. These data indicate that L-PGDS/β-trace is a major endogenous Aβ-chaperone in the brain and suggest that the disturbance of this function may be involved in the onset and progression of AD. Our findings may provide a diagnostic and therapeutic approach for AD.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0701585104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
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    Online Resource
    Neuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain
    Society for Neuroscience ; 2015
    In:  The Journal of Neuroscience Vol. 35, No. 14 ( 2015-04-08), p. 5851-5859
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 35, No. 14 ( 2015-04-08), p. 5851-5859
    Abstract: Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5180-14.2015
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2015
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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