-
Justin T Rogers,
Lisa Zhao,
Justin H Trotter,
Ian Rusiana,
Melinda M Peters,
Qingyou Li,
Erika Donaldson,
Jessica L Banko,
Kathleen E Keenoy,
G William Rebeck, Hyang-Sook Hoe,
Gabriella D'Arcangelo,
Edwin J Weeber
[show abstract]
[hide abstract]
ABSTRACT: The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults.
Journal of Psychopharmacology 10/2012; · 3.04 Impact Factor
-
Justin T Rogers,
Ian Rusiana,
Justin Trotter,
Lisa Zhao,
Erika Donaldson,
Daniel T S Pak,
Lenard W Babus,
Melinda Peters,
Jessica L Banko,
Pascale Chavis,
G William Rebeck, Hyang-Sook Hoe,
Edwin J Weeber
-
You Me Sung,
Taehee Lee,
Hyejin Yoon,
Amanda Marie Dibattista,
Jungmin Song,
Yoojin Sohn,
Emily Isabella Moffat,
R Scott Turner,
Mira Jung,
Jungsu Kim, Hyang-Sook Hoe
[show abstract]
[hide abstract]
ABSTRACT: Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β- and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.
Experimental Neurology 10/2012; · 4.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Apolipoprotein J (apoJ), also known as clusterin and SP-40,40, binds soluble beta-amyloid (Aβ and is up-regulated in the Alzheimer’s
disease (AD) brain. In the present study we classified apoJ-immunopositive Aβ deposits in AD temporal cortex, and found apoJ-immunoreactive
plaques were often associated with dystrophic neurites. Quantitative immunohistochemical analysis of five AD brains showed
that 29% of Aβ deposited in the parenchyma was associated with apoJ. Of Aβ deposits with apoJ immunopositivity, 71% were associated
with phospho-tau-positive dystrophic neurites in the surrounding tissue. Conversely, 64% of phospho-tau-labeled neuritic deposits
were labeled with apoJ. ApoJ was found at the core of these deposits, and co-localized with the amyloid staining agent thioflavine-S.
To test the direct effects of apoJ on tau metabolism, we treated cells in culture with apoJ-containing conditioned media,
and we injected apoJ-containing media into the rat hippocampus. Using both systems, we observed increases in levels of tau
and phosphorylated tau. Our findings demonstrate that apoJ immunopositivity strongly correlates with the presence of amyloid
and associated neuritic dystrophy in the neuropil of AD temporal cortex, and supports a model where extracellular apoJ facilitates
the conversion of diffuse Aβ deposits into amyloid and enhances tau phosphorylation in neurites surrounding these plaques.
Neurotoxicity Research 04/2012; 7(3):231-241. · 3.51 Impact Factor
-
Sonya B Dumanis,
Kelly A Chamberlain,
Yoo Jin Sohn,
Young Jin Lee,
Suzanne Y Guénette,
Toshiharu Suzuki,
Paul M Mathews,
Daniel Ts Pak,
G William Rebeck,
Yoo-Hun Suh,
Hee-Sae Park, Hyang-Sook Hoe
[show abstract]
[hide abstract]
ABSTRACT: Several studies found that FE65, a cytoplasmic adaptor protein, interacts with APP and LRP1, altering the trafficking and processing of APP. We have previously shown that FE65 interacts with the ApoE receptor, ApoER2, altering its trafficking and processing. Interestingly, it has been shown that FE65 can act as a linker between APP and LRP1 or ApoER2. In the present study, we tested whether FE65 can interact with another ApoE receptor, VLDLR, thereby altering its trafficking and processing, and whether FE65 can serve as a linker between APP and VLDLR.
We found that FE65 interacted with VLDLR using GST pull-down and co-immunoprecipitation assays in COS7 cells and in brain lysates. This interaction occurs via the PTB1 domain of FE65. Co-transfection with FE65 and full length VLDLR increased secreted VLDLR (sVLDLR); however, the levels of VLDLR C-terminal fragment (CTF) were undetectable as a result of proteasomal degradation. Additionally, FE65 increased cell surface levels of VLDLR. Moreover, we identified a novel complex between VLDLR and APP, which altered trafficking and processing of both proteins. Furthermore, immunoprecipitation results demonstrated that the presence of FE65 increased the interaction between APP and VLDLR in vitro and in vivo.
These data suggest that FE65 can regulate VLDLR trafficking and processing. Additionally, the interaction between VLDLR and APP altered both protein's trafficking and processing. Finally, our data suggest that FE65 serves as a link between VLDLR and APP. This novel interaction adds to a growing body of literature indicating trimeric complexes with various ApoE Receptors and APP.
Molecular Neurodegeneration 03/2012; 7:9. · 4.28 Impact Factor
-
Molecular Neurodegeneration 02/2012; 7 Suppl 1:O5. · 4.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ATP-binding cassette transporter A1 (ABCA1) is a cholesterol transporter that transfers excess cellular cholesterol onto lipid-poor apolipoproteins. Given its critical role in cholesterol homeostasis, ABCA1 has been studied as a therapeutic target for Alzheimer's disease. Transcriptional regulation of ABCA1 by liver X receptor has been well characterized. However, whether ABCA1 expression is regulated at the posttranscriptional level is largely unknown. Identification of a novel pathway that regulates ABCA1 expression may provide new strategy for regulating cholesterol metabolism and amyloid β (Aβ) levels. Since ABCA1 has an unusually long 3' untranslated region, we investigated whether microRNAs could regulate ABCA1 expression. We identified miR-106b as a novel regulator of ABCA1 expression and Aβ metabolism. miR-106b significantly decreased ABCA1 levels and impaired cellular cholesterol efflux in neuronal cells. Furthermore, miR-106b dramatically increased levels of secreted Aβ by increasing Aβ production and preventing Aβ clearance. Alterations in Aβ production and clearance were rescued by expression of miR-106b-resistant ABCA1. Taken together, our data suggest that miR-106b affects Aβ metabolism by suppressing ABCA1 expression.
Experimental Neurology 11/2011; 235(2):476-83. · 4.70 Impact Factor
-
Justin T Rogers,
Ian Rusiana,
Justin Trotter,
Lisa Zhao,
Erika Donaldson,
Daniel T S Pak,
Lenard W Babus,
Melinda Peters,
Jessica L Banko,
Pascale Chavis,
G William Rebeck, Hyang-Sook Hoe,
Edwin J Weeber
[show abstract]
[hide abstract]
ABSTRACT: Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.
Learning & memory (Cold Spring Harbor, N.Y.) 09/2011; 18(9):558-64. · 4.08 Impact Factor
-
Lenard W Babus,
Elizabeth M Little,
Kathleen E Keenoy,
S Sakura Minami,
Eric Chen,
Jung Min Song,
Juliet Caviness,
So-Yeon Koo,
Daniel T S Pak,
G William Rebeck,
R Scott Turner, Hyang-Sook Hoe
[show abstract]
[hide abstract]
ABSTRACT: Fyn is a Src-family tyrosine kinase that affects long term potentiation (LTP), synapse formation, and learning and memory. Fyn is also implicated in dendritic spine formation both in vitro and in vivo. However, whether Fyn's regulation of dendritic spine formation is brain-region specific and age-dependent is unknown. In the present study, we systematically examined whether Fyn altered dendritic spine density and morphology in the cortex and hippocampus and if these effects were age-dependent. We found that Fyn knockout mice trended toward a decrease in dendritic spine density in cortical layers II/III, but not in the hippocampus, at 1 month of age. Additionally, Fyn knockout mice had significantly decreased dendritic spine density in both the cortex and hippocampus at 3 months and 1 year, and Fyn's effect on dendritic spine density was age-dependent in the hippocampus. Moreover, Fyn knockout mice had wider spines at the three time points (1 month, 3 months, 1 year) in the cortex. These findings suggest that Fyn regulates dendritic spine number and morphology over time and provide further support for Fyn's role in maintaining proper synaptic function in vivo.
Brain research 08/2011; 1415:96-102. · 2.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fyn kinase phosphorylates tau and exacerbates amyloid beta (Aβ)-mediated synaptic dysfunction. However, Fyn also increases the nonpathological cleavage of amyloid precursor protein (APP), suggesting opposing roles for Fyn in the pathogenesis of Alzheimer's disease (AD). To determine the effect of Fyn on both Aβ and tau pathologies, we crossed homozygous Alzheimer's disease triple transgenic (3×Tg) mice harboring mutations in amyloid precursor protein, presenilin-1, and tau with wild-type or Fyn knockout mice to generate Fyn(+/+)3×Tg(+/-) or Fyn(+/-)3×Tg(+/-) mice. We found that Fyn(+/-)3×Tg(+/-) mice had increased soluble and intracellular Aβ, and these changes were accompanied by impaired performance on the Morris water maze at 18 months. Fyn(+/-)3×Tg(+/-) mice had decreased phosphorylated tau at 15-18 months (as did Fyn knockout mice), but Fyn(+/-)3×Tg(+/-) mice had increased phosphorylated tau by 24 months. In addition, we observed that Fyn(+/-)3×Tg(+/-) males were delayed in developing Aβ pathology compared with females, and displayed better spatial learning performance at 18 months. Overall, these findings suggest that loss of Fyn at early stages of disease increases soluble Aβ accumulation and worsens spatial learning in the absence of changes in tau phosphorylation.
Neurobiology of aging 07/2011; 33(4):825.e15-24. · 5.94 Impact Factor
-
Mi-Yeon Kim,
Jung-Soon Mo,
Eun-Jung Ann,
Ji-Hye Yoon,
Jane Jung,
Yun-Hee Choi,
Su-Man Kim,
Hwa-Young Kim,
Ji-Seon Ahn,
Hangun Kim,
Kwonseop Kim, Hyang-Sook Hoe,
Hee-Sae Park
[show abstract]
[hide abstract]
ABSTRACT: The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.
Journal of Cell Science 06/2011; 124(Pt 11):1831-43. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The adaptor protein Disabled1 (Dab1) interacts with amyloid precursor protein (APP) and decreases its pathological processing, an effect mediated by Fyn tyrosine kinase. Fyn is highly enriched in lipid rafts, a major site of pathological APP processing. To investigate the role of Fyn in the localization and phosphorylation of APP and Dab1 in lipid rafts, we isolated detergent-resistant membrane (DRM) fractions from wild-type and Fyn knock-out mice. In wild-type mice, all of the Fyn kinase, 17% of total APP, and 33% of total Dab1 were found in DRMs. Nearly all of the tyrosine phosphorylated forms of APP and Dab1 were in DRMs. APP and Dab1 co-precipitated both in and out of DRM fractions, indicating an association that is independent of subcellular localization. Fyn knock-out mice had decreased APP, Dab1, and tyrosine-phosphorylated Dab1 in DRMs but increased co-immunoprecipitation of DRM APP and Dab1. Expression of phosphorylation deficient APP or Dab1 constructs revealed that phosphorylation of APP increases, whereas phosphorylation of Dab1 decreases, the interaction between APP and Dab1. Consistent with these observations, Reelin treatment led to increased Dab1 phosphorylation and decreased association between APP and Dab1. Reelin also caused increased localization of APP and Dab1 to DRMs, an effect that was not seen in Fyn knock-out neurons. These findings suggest that Reelin treatment promotes the localization of APP and Dab1 to DRMs, and affects their phosphorylation by Fyn, thus regulating their interaction.
Journal of Neurochemistry 05/2011; 118(5):879-90. · 4.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Intraneuronal amyloid-β (Aβ) may contribute to extracellular plaque deposition, the characteristic pathology of Alzheimer's disease (AD). The E3-ubiquitin ligase parkin ubiquitinates intracellular proteins and induces mitophagy. We previously demonstrated that parkin reduces Aβ levels in lentiviral models of intracellular Aβ. Here we used a triple transgenic AD (3xTg-AD) mouse, which over-expresses APP(Swe), Tau(P301L) and harbor the PS1(M146V) knock-in mutation and found that lentiviral parkin ubiquitinated intracellular Aβ in vivo, stimulated beclin-dependent molecular cascade of autophagy and facilitated clearance of vesicles containing debris and defective mitochondria. Parkin expression decreased intracellular Aβ levels and extracellular plaque deposition. Parkin expression also attenuated caspase activity, prevented mitochondrial dysfunction and oxidative stress and restored neurotransmitter synthesis. Restoration of glutamate synthesis, which was independent of glial-neuronal recycling, depended on mitochondrial activity and led to an increase in γ-amino butyric acid levels. These data indicate that parkin may be used as an alternative strategy to reduce Aβ levels and enhance autophagic clearance of Aβ-induced defects in AD. Parkin-mediated clearance of ubiquitinated Aβ may act in parallel with autophagy to clear molecular debris and defective mitochondria and restore neurotransmitter balance.
Human Molecular Genetics 03/2011; 20(11):2091-102. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
Neuron 03/2011; 69(5):957-73. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Traumatic brain injury (TBI) increases brain beta-amyloid (Aβ) in humans and animals. Although the role of Aβ in the injury cascade is unknown, multiple preclinical studies have demonstrated a correlation between reduced Aβ and improved outcome. Therefore, therapeutic strategies that enhance Aβ clearance may be beneficial after TBI. Increased levels of ATP-binding cassette A1 (ABCA1) transporters can enhance Aβ clearance through an apolipoprotein E (apoE)-mediated pathway. By measuring Aβ and ABCA1 after experimental TBI in C57BL/6J mice, we found that Aβ peaked early after injury (1-3 days), whereas ABCA1 had a delayed response (beginning at 3 days). As ABCA1 levels increased, Aβ levels returned to baseline levels-consistent with the known role of ABCA1 in Aβ clearance. To test if enhancing ABCA1 levels could block TBI-induced Aβ, we treated TBI mice with the liver X-receptor (LXR) agonist T0901317. Pre- and post-injury treatment increased ABCA1 levels at 24 h post-injury, and reduced the TBI-induced increase in Aβ. This reduction in Aβ was not due to decreased amyloid precursor protein processing, or a shift in the solubility of Aβ, indicating enhanced clearance. T0901317 also limited motor coordination deficits in injured mice and reduced brain lesion volume. These data indicate that activation of LXR can reduce Aβ accumulation after TBI, and is accompanied by improved functional recovery.
Journal of neurotrauma 02/2011; 28(2):225-36. · 4.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We recently identified the activity-inducible protein kinase Plk2 as a novel overseer of the balance between Ras and Rap small GTPases. Plk2 achieves a profound level of regulatory control by interacting with and phosphorylating at least four Ras and Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Combined, these actions result in synergistic suppression of Ras and hyperstimulation of Rap signaling. Perturbation of Plk2 function abolished homeostatic adaptation of synapses to enhanced activity and impaired behavioral adaptation in various learning tasks, indicating that this regulation was critical for maintaining appropriate Ras/Rap levels. These studies provide insights into the highly cooperative nature of Ras and Rap regulation in neurons. However, different GEF and GAP substrates of Plk2 also controlled specific aspects of dendritic spine morphology, illustrating the ability of individual GAPs/GEFs to assemble microdomains of Ras and Rap signaling that respond to different stimuli and couple to distinct output pathways.
Small GTPases 01/2011; 2(3):162-166.
-
Sonya B Dumanis,
Hyun-Jung Cha,
Jung Min Song,
Justin H Trotter,
Matthew Spitzer,
Ji-Yun Lee,
Edwin J Weeber,
R Scott Turner,
Daniel T S Pak,
G William Rebeck, Hyang-Sook Hoe
[show abstract]
[hide abstract]
ABSTRACT: Apolipoprotein E receptor 2 (ApoEr2) is a postsynaptic protein involved in long-term potentiation (LTP), learning, and memory through unknown mechanisms. We examined the biological effects of ApoEr2 on synapse and dendritic spine formation-processes critical for learning and memory.
In a heterologous co-culture synapse assay, overexpression of ApoEr2 in COS7 cells significantly increased colocalization with synaptophysin in primary hippocampal neurons, suggesting that ApoEr2 promotes interaction with presynaptic structures. In primary neuronal cultures, overexpression of ApoEr2 increased dendritic spine density. Consistent with our in vitro findings, ApoEr2 knockout mice had decreased dendritic spine density in cortical layers II/III at 1 month of age. We also tested whether the interaction between ApoEr2 and its cytoplasmic adaptor proteins, specifically X11α and PSD-95, affected synapse and dendritic spine formation. X11α decreased cell surface levels of ApoEr2 along with synapse and dendritic spine density. In contrast, PSD-95 increased cell surface levels of ApoEr2 as well as synapse and dendritic spine density.
These results suggest that ApoEr2 plays important roles in structure and function of CNS synapses and dendritic spines, and that these roles are modulated by cytoplasmic adaptor proteins X11α and PSD-95.
PLoS ONE 01/2011; 6(2):e17203. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The memory dysfunctions that characterize Alzheimer's disease (AD) are strongly correlated with synapse loss. The amyloid precursor protein (APP) and its cleavage product Aβ play central roles in synapse and memory loss, and thus are strongly implicated in the pathogenesis of AD. Numerous in vitro and transgenic AD mouse model studies have shown that overexpression of APP leads to Aβ accumulation, which causes decreased synaptic activity and dendritic spine density. However, the normal synaptic function of APP itself is not fully understood. Several recent studies have found that full-length APP promotes synaptic activity, synapse formation, and dendritic spine formation. These findings cast APP as a potential key player in learning and memory. It is of interest that the synaptic functions of full-length APP are opposite to the effects associated with pathological Aβ accumulation. In this review, we will summarize the normal functions of APP at synapses and spines along with other known functions of APP, including its role in cell motility, neuronal migration, and neurite outgrowth. These studies shed light on the physiological actions of APP, independent of Aβ effects, and thus lead to a better understanding of the synaptic dysfunctions associated with AD.
CNS Neuroscience & Therapeutics 12/2010; 18(1):47-56. · 4.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.
Nature Neuroscience 10/2010; 13(10):1199-207. · 15.53 Impact Factor
-
S Sakura Minami,
Elkhansa Sidahmed,
Saba Aid,
Mika Shimoji,
Takako Niikura,
Italo Mocchetti,
G William Rebeck,
Jay S Prendergast,
Chris Dealwis,
Ronald Wetzel,
Francesca Bosetti,
Yasuji Matsuoka, Hyang-Sook Hoe,
R Scott Turner
[show abstract]
[hide abstract]
ABSTRACT: Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema).
We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month) male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization.
The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1.
These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines.
Journal of Neuroinflammation 09/2010; 7:57. · 3.83 Impact Factor
