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• W2075725519 abstract "Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-β (Aβ) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Aβ pathology. We describe improved cognitive function following a reduction in both soluble Aβ and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Aβ alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Aβ immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice. Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-β (Aβ) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Aβ pathology. We describe improved cognitive function following a reduction in both soluble Aβ and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Aβ alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Aβ immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice. Alzheimer disease (AD) 2The abbreviations used are: AD, Alzheimer disease; Aβ, amyloid-β; NFT, neurofibrillary tangles; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; TNF, tumor necrosis factor. is clinically marked by a progressive deterioration of memory and other cognitive functions. Two obligate neuropathological lesions occur in the AD brain: amyloid plaques, mainly formed by a small peptide called amyloid-β (Aβ), and neurofibrillary tangles (NFTs) formed by the hyperphosphorylated microtubule-binding protein tau (1Selkoe D.J. Physiol. Rev. 2001; 81: 741-766Crossref PubMed Scopus (5170) Google Scholar). The accumulation of Aβ plays a central role in the progression of the disease, and over the past several years, there has been a growing appreciation for the pathogenic effects of soluble assemblies of Aβ, which may be the predominant toxic species for neurons (2Cleary J.P. Walsh D.M. Hofmeister J.J. Shankar G.M. Kuskowski M.A. Selkoe D.J. Ashe K.H. Nat. Neurosci. 2005; 8: 79-84Crossref PubMed Scopus (1493) Google Scholar, 3Lesne S. Koh M.T. Kotilinek L. Kayed R. Glabe C.G. Yang A. Gallagher M. Ashe K.H. Nature. 2006; 440: 352-357Crossref PubMed Scopus (2430) Google Scholar, 4Walsh D.M. Selkoe D.J. Neuron. 2004; 44: 181-193Abstract Full Text Full Text PDF PubMed Scopus (1055) Google Scholar). The causes underlying AD-related memory loss and other cognitive changes are likely to be multifactorial, and although evidence suggests that soluble Aβ is an excellent candidate to be the initial trigger (4Walsh D.M. Selkoe D.J. Neuron. 2004; 44: 181-193Abstract Full Text Full Text PDF PubMed Scopus (1055) Google Scholar), other elements of AD neuropathology almost certainly contribute to the progressive deterioration in the cognitive faculties. In this regard, it is likely that the manifestation of tau pathology plays a pivotal role that further exacerbates the cognitive decline in the presence of Aβ and other AD-related alterations. Pathological assemblies of tau can induce neurodegeneration and dementia in the absence of Aβ, as occurs in disorders such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17) (5Cairns N.J. Lee V.M. Trojanowski J.Q. J. Pathol. 2004; 204: 438-449Crossref PubMed Scopus (143) Google Scholar). Elucidating the relationship between these two proteins (Aβ and tau) and their synergistic effects on cognition is facilitated by the utilization of a transgenic model that develops both Aβ and tau pathology. The 3xTg-AD mice develop an age-dependent decline in the cognitive phenotype in both spatial and contextual learning and memory paradigms. The occurrence of intraneuronal Aβ appears to be a trigger for the onset of deficits in water maze spatial memory, an effect that is fully reversible by Aβ immunotherapy (6Billings L.M. Oddo S. Green K.N. McGaugh J.L. LaFerla F.M. Neuron. 2005; 45: 675-688Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar). However, as the mice age and extracellular Aβ and neurofibrillary pathology manifest, the mice show further cognitive decline, 3L. M. Billings, K. N. Green, J. L. McGaugh, and F. M. LaFerla, submitted manuscript. although the role that plaques and tangles play on the deterioration of the cognitive phenotype is still unresolved. Postmortem evaluation of AD brains has provided some correlational evidence linking these structures to the cognitive decline, with the general finding that tangles are a better correlate than plaques (7Arriagada P.V. Marzloff K. Hyman B.T. Neurology. 1992; 42: 1681-1688Crossref PubMed Google Scholar, 8McKee A.C. Kosik K.S. Kowall N.W. Ann. Neurol. 1991; 30: 156-165Crossref PubMed Scopus (334) Google Scholar). However, these types of studies have two inherent limitations. 1) They ignore the dynamic nature of clearance mechanisms; thus, it is possible that the guilty culprit (e.g. plaque or NFT) that induces cognitive decline is no longer present in the brain at the time of autopsy. 2) It is now recognized that soluble Aβ assemblies may directly cause cognitive dysfunction. Moreover, it remains to be established if and how soluble tau accumulation participates in the cognitive decline in the presence of Aβ pathology, which represents the focus of this study. Although increasing evidence suggests that soluble Aβ may be a key factor in inducing cognitive decline, to our knowledge, no firm experimental evidence has been presented to show a comparable role for soluble tau in an experimental mammalian system, particularly in the presence of Aβ pathology. A prior study involving regulatable tau transgenic mice found that NFTs are not sufficient to induce memory loss and neuronal loss, but no mechanism was defined or proposed (9Santacruz K. Lewis J. Spires T. Paulson J. Kotilinek L. Ingelsson M. Guimaraes A. DeTure M. Ramsden M. McGowan E. Forster C. Yue M. Orne J. Janus C. Mariash A. Kuskowski M. Hyman B. Hutton M. Ashe K.H. Science. 2005; 309: 476-481Crossref PubMed Scopus (1566) Google Scholar). Aβ immunotherapy, both active and passive, has been shown to be a valuable tool to decrease Aβ pathology and rescue cognitive deficits in several AD transgenic models (10Schenk D. Barbour R. Dunn W. Gordon G. Grajeda H. Guido T. Hu K. Huang J. Johnson-Wood K. Khan K. Kholodenko D. Lee M. Liao Z. Lieberburg I. Motter R. Mutter L. Soriano F. Shopp G. Vasquez N. Vandevert C. Walker S. Wogulis M. Yednock T. Games D. Seubert P. Nature. 1999; 400: 173-177Crossref PubMed Scopus (2953) Google Scholar, 11Morgan D. Diamond D.M. Gottschall P.E. Ugen K.E. Dickey C. Hardy J. Duff K. Jantzen P. DiCarlo G. Wilcock D. Connor K. Hatcher J. Hope C. Gordon M. Arendash G.W. Nature. 2000; 408: 982-985Crossref PubMed Scopus (1427) Google Scholar, 12Janus C. Pearson J. McLaurin J. Mathews P.M. Jiang Y. Schmidt S.D. Chishti M.A. Horne P. Heslin D. French J. Mount H.T. Nixon R.A. Mercken M. Bergeron C. Fraser P.E. St George-Hyslop P. Westaway D. Nature. 2000; 408: 979-982Crossref PubMed Scopus (1377) Google Scholar, 13DeMattos R.B. Bales K.R. Cummins D.J. Dodart J.C. Paul S.M. Holtzman D.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8850-8855Crossref PubMed Scopus (1195) Google Scholar, 14Bard F. Cannon C. Barbour R. Burke R.L. Games D. Grajeda H. Guido T. Hu K. Huang J. Johnson-Wood K. Khan K. Kholodenko D. Lee M. Lieberburg I. Motter R. Nguyen M. Soriano F. Vasquez N. Weiss K. Welch B. Seubert P. Schenk D. Yednock T. Nat. Med. 2000; 6: 916-919Crossref PubMed Scopus (1811) Google Scholar). Although the human clinical trial involving an active immunization approach was suspended because 6% of the patients developed meningoencephalitis (15Check E. Nature. 2002; 415: 462Crossref PubMed Scopus (173) Google Scholar) this strategy still holds great potential because it is a disease-modifying intervention, in contrast with currently available treatments (16Nitsch R.M. Alzheimer Dis. Assoc. Disord. 2004; 18: 185-189PubMed Google Scholar, 17Schenk D. Nat. Rev. Neurosci. 2002; 3: 824-828Crossref PubMed Scopus (417) Google Scholar). A critical issue that remains to be resolved is whether therapeutic interventions aimed at decreasing Aβ will suffice to improve cognition in the presence of established plaques and NFTs. Here we actively or passively immunized aged 3xTg-AD mice to determine whether it was possible to ameliorate their cognitive impairments in the presence of established plaques and NFTs. We report that reduction of both soluble Aβ and tau levels were required to rescue the cognitive impairments. Notably, decreasing soluble Aβ without affecting soluble tau levels did not improve cognition. Therefore, we conclude that Aβ immunotherapy represents an effective strategy for ameliorating cognitive decline even in aged brains marked by resistant amyloid plaques and NFTs. Moreover, these data suggest that soluble tau plays an important role in the cognitive impairments in aged 3xTg-AD mice and by extrapolation independent therapies aimed at further reducing its levels or restoring tau function may lead to even greater cognitive improvements in human patients. Immunization—For active immunization, Aβ42 peptide was synthesized at the University of California Core Facility, and fibrillar Aβ42 (fAβ42) was prepared as previously described (18Cribbs D.H. Ghochikyan A. Vasilevko V. Tran M. Petrushina I. Sadzikava N. Babikyan D. Kesslak P. Kieber-Emmons T. Cotman C.W. Agadjanyan M.G. Int. Immunol. 2003; 15: 505-514Crossref PubMed Scopus (257) Google Scholar) and delivered subcutaneously (s.c.). Blood was collected before the first immunization and 10 days after each boost from the retro-orbital sinus into EDTA-coated tubes. Tubes were centrifuged for 10 min at 4 °C, and the sera were collected as a supernatant and stored at -80 °C. For passive immunization, the mouse anti-Aβ monoclonal 20.1 antibody was prepared in low endotoxin format from a hybridoma kindly provided by Dr. William Van Nostrand (Stony Brook University, Stony Brook, NY). The 20.1 antibody is an IgG2b isotype and recognizes the N-terminal region of Aβ spanning amino acids 1-8. Mice were given weekly intraperitoneal injections of 300 μg of 20.1 antibody diluted in 300 μl of phosphate-buffered saline. Sera from the mice were collected before and at 24 h and 7 days after administration of the antibody, as well as at the end of experiment. The anti-Aβ antibody concentration as well as Aβ40 and Aβ42 peptide concentration were measured. Behavior—The passive inhibitory avoidance was conducted as previously described (6Billings L.M. Oddo S. Green K.N. McGaugh J.L. LaFerla F.M. Neuron. 2005; 45: 675-688Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar). The T-maze consisted of a central main arm with two side arms positioned perpendicular to the main arm. The central arm was 65-cm long, and the two side arms were 30-cm each. The maze width was 13.5 cm. The walls of the maze were made of transparent acrylic and were 20-cm tall. At the beginning of each test, the mice were placed in the main stem while one side arm was blocked by a barrier so that the mice were forced to make a choice. Once the mice entered the side arm, the entrance was blocked, thus retaining them in the side arm. Mice were left to explore that arm for 120 s at the end of which they were placed back in the main arm of the maze with both side arms open. Mice were free to choose the arm that they already explored or the new arm. Each animal was tested daily for 7 days and on each day we alternatively blocked one side arm. The numbers of alternations and the latency to make a choice during the free trial were recorded. Immunological and Histological Staining—After completion of the behavioral tasks, the mice were trans-cardially perfused with ice-cold PBS. Following perfusion, each brain was cut sagittally, and one-half of the brain was frozen in dry ice whereas the other half was fixed in ice-cold paraformaldehyde for 48 h. After fixation, brains were cut (50-μm thick) using a slicing vibratome (Pelco, Redding, CA), and sections were stored in 0.02% sodium azide in PBS. Immunohistochemical analysis was conducted as previously described (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar). For thioflavine staining, sections were incubated in a 0.5% solution of ThioflavineS (Sigma Aldrich) in 50% ethanol for 10 min. Sections were then washed twice for 3 min each in 50% ethanol and twice for 3 min each in water. Quantification of the stained sections was done as previously described (20Oddo S. Caccamo A. Smith I.F. Green K.N. Laferla F.M. Am. J. Pathol. 2006; 168: 184-194Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Western Blot and ELISA—Brains were homogenized in Tissue Protein Extraction reagent (Pierce) supplemented with a complete mini protease inhibitor tablet (Roche Applied Science) and phosphatase inhibitors (Calbiochem, San Diego, CA). The homogenized mixes were briefly sonicated to sheer the DNA and centrifuged at 4 °C for 1 h at 100,000 × g. The supernatant was stored as the soluble fraction. The pellet was re-homogenized in 70% formic acid and centrifuged at 4 °C for 1 h at 100,000 × g. The supernatant was stored as the insoluble fraction. The extraction procedure was confirmed by Western blot, using APP as a marker of soluble proteins and flotillin as a marker of insoluble proteins (data not shown). Protein concentration was determined using the Bio-Rad protein assay, and samples were adjusted with T-PER to the same concentration. Western blot and Aβ ELISA experiments were done as previously described (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar, 21Oddo S. Caccamo A. Green K.N. Liang K. Tran L. Chen Y. Leslie F.M. LaFerla F.M. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 3046-3051Crossref PubMed Scopus (171) Google Scholar). ELISA measurements of tau were conducted using a total tau ELISA kit from BIOSOURCE (Camarillo, CA) in accordance with the manufacturer's instructions. The titers of anti-Aβ antibodies were measured as previously described (18Cribbs D.H. Ghochikyan A. Vasilevko V. Tran M. Petrushina I. Sadzikava N. Babikyan D. Kesslak P. Kieber-Emmons T. Cotman C.W. Agadjanyan M.G. Int. Immunol. 2003; 15: 505-514Crossref PubMed Scopus (257) Google Scholar). Quantitative Cytokine Assay—Levels of different cytokines were quantitatively measured by Bio-Plex 200 (Bio-Rad) system using the manufacturer's instructions. Antibodies—The following antibodies were used in this study: anti-Aβ 6E10 (Signet Laboratories, Dedham, MA), anti-Aβ 1560 (Chemicon, Temecula, CA), anti-Aβ40 and anti Aβ42 (BIOSOURCE, Camarillo, CA), anti-Aβ 35-40 (MM32-13.1.1, for Aβ40) or anti-Aβ 35-42 (MM40-21.3.4, for Aβ42), anti-β-actin (Sigma), anti-tau HT7, (Innogenetics, Belgium), AT8 and AT100 (Pierce), 8C11 and 16B5 were a generous gift from Dr. Peter Seubert. HT7, 8C11, and 16B5 recognize tau independent of its phosphorylation state. Statistical Analysis—Data were analyzed using one-way analysis of variance (ANOVA) with Bonferoni post-test using GraphPad Prism version 3.00 for Windows, GraphPad Software, San Diego, CA. We first sought to determine whether aged mice harboring an extensive plaque and tangle burden would show improved learning and memory following active or passive Aβ immunization. For the active immunization study, thirty 18-month-old 3xTg-AD mice were randomly assigned to one of three groups: 1) untreated, 2) adjuvant only, and 3) fibrillar Aβ42. For the passive immunization, ten 20-month-old 3xTg-AD mice received 300 μg per injection of the anti-Aβ antibody 20.1, which is raised against the first 8 amino acids of the Aβ sequence. The active immunization trial was conducted over a period of 5 months, whereas the passive immunization trial was conducted over a period of 3 months (Fig. 1A). Consequently, all the mice were 23 months old at the conclusion of the experiment. Mice, actively immunized with fAβ42 had significant amounts of circulating anti-Aβ antibody (82.95 ± 37.09 μg/ml) after four injections and maintained uniform elevated levels of anti-Aβ antibodies. The antibody concentration 10 days after the last injection was 101.28 ± 63.61 μg/ml. In contrast, adjuvant-treated or unimmunized mice did not have detectable levels of anti-Aβ antibody during the experiment (data not shown). Average serum titers from the passively immunized mice were 1:53,000 and 1:5,400 at 24-h and 7-days postinjection, respectively. Aβ Vaccination Ameliorates the Behavioral Phenotype despite Persistent Plaques and NFTs—At the end of the treatment period, we evaluated the behavioral phenotype of the 3xTg-AD mice using two different behavioral paradigms, the T-maze and the passive inhibitory avoidance. The former relies on the tendency of mice to alternate free choices in a T-maze during successive trials, and it is mainly based on working memory and is dependent on several brain regions including the basal forebrain, hippocampus, and prefrontal cortex (22Lalonde R. Neurosci. Biobehav Rev. 2002; 26: 91-104Crossref PubMed Scopus (578) Google Scholar). The passive inhibitory avoidance is a contextual learning and memory task, which is mainly dependent on the amygdala (23McGaugh J.L. McIntyre C.K. Power A.E. Neurobiol. Learn. Mem. 2002; 78: 539-552Crossref PubMed Scopus (233) Google Scholar). Aged 3xTg-AD mice that were either untreated or treated with adjuvant only performed at chance levels on the T-maze, i.e. they failed to alternate between the two arms of the maze on successive trials (47.6 ± 2.4% and 46.4 ± 5.2%, respectively, Fig. 1B). In contrast, we found that the percentage of alternations was significantly increased in both actively and passively immunized 3xTg-AD mice (63.5 ± 6.8% and 64.3 ± 2.7%, respectively, Fig. 1B) and was similar to that of age-matched non transgenic (NonTg) mice (71.43 ± 3.37% Fig. 1B). As the ability to successfully alternate with each successive trial is considered to reflect intact working memory (22Lalonde R. Neurosci. Biobehav Rev. 2002; 26: 91-104Crossref PubMed Scopus (578) Google Scholar), these results show that working memory can be restored in aged transgenic mice following active or passive immunization. We next evaluated the mice on a contextual learning and memory task using passive inhibitory avoidance. During the initial training and the subsequent 3-h probe trial, all the groups performed similarly (p < 0.05, Fig. 1C), indicating that the task was learned and retained during the first 3 h. For the 24-h probe, both control groups showed a reduced latency to cross over to the dark compartment, although the results did not achieve statistical significance compared with immunized mice (Fig. 1C). In contrast, analysis at the 36-h probe trial indicated that both the active and passive immunized groups performed similarly to NonTg mice (162.9 ± 17.1, 150.2 ± 19.8, and 173.9 ± 2.8 s), and significantly better than the unimmunized control groups (79.28 ± 17.5 and 93.1 ± 18 s, for untreated and adjuvant treated mice, respectively; Fig. 1C). These results clearly indicate that 23-month-old 3xTg-AD mice can learn and briefly retain this information for the short term, but cannot form long term memories (i.e. 36 h), whereas immunized mice are able to retain the information throughout the duration of the experiment. Reduction of Soluble Aβ Levels by Active and Passive Immunization—We next determined the effect of active and passive immunization on plaque burden in the aged mice. The number of thioflavine-positive plaques did not appear to be statistically reduced in aged 3xTg-AD mice immunized with fAβ42, as the overall burden was similar to the control groups (Fig. 2, A-D). In contrast, the number of thioflavine-positive plaques was significantly reduced in aged 3xTg-AD mice passively immunized (Fig. 2, E and F). The number of plaques per microscopic field was 29 ± 2.8 S.E., 29 ± 2.2 S.E., and 15 ± 2.1 S.E., for the adjuvant, active, and passive immunized mice, respectively (Fig. 2G). Although the number of thioflavine-positive plaques was not significantly reduced in actively immunized mice, we still found that these mice performed significantly better than control mice in both the T-maze and the passive inhibitory avoidance tasks. Consequently, we analyzed brain extracts from these mice by sandwich ELISA to determine if total Aβ levels were reduced. Among all the groups analyzed, insoluble Aβ40 and Aβ42 were only significantly reduced in passively immunized mice (Fig. 2H), consistent with the immunohistochemical results. Notably, soluble Aβ42 levels were significantly lower in both the actively and passively immunized mice (Fig. 2H), whereas soluble Aβ40 levels were significantly decreased following passive immunization but not with active immunization (Fig. 2H). As the reduction of soluble Aβ42 levels was the only species of Aβ consistently changed among all the immunized mice, it indicates that lowering this Aβ species even in mice with extensive plaque and tangle neuropathology can lead to improvements in cognition. These results are consistent with recent data showing that soluble Aβ better correlates with memory impairments in AD patients and transgenic mice (6Billings L.M. Oddo S. Green K.N. McGaugh J.L. LaFerla F.M. Neuron. 2005; 45: 675-688Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar, 24Kawarabayashi T. Shoji M. Younkin L.H. Wen-Lang L. Dickson D.W. Murakami T. Matsubara E. Abe K. Ashe K.H. Younkin S.G. J. 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A. 1999; 96: 3228-3233Crossref PubMed Scopus (991) Google Scholar). Reduction of Soluble but Not Insoluble Tau by Active and Passive Immunization—Because we immunized aged mice with very extensive plaque and tangle pathology, we next determined whether active or passive immunization had any beneficial downstream effects on the tau pathology. Although our previous studies showed that a single intrahippocampal injection of Aβ antibodies was able to reduce early, but not late hyperphosphorylated/aggregated tau in 1-year-old mice (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar, 30Oddo S. Caccamo A. Tran L. Lambert M.P. Glabe C.G. Klein W.L. LaFerla F.M. J. Biol. Chem. 2006; 281: 1599-1604Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar), it remains to be established whether active or chronic passive immunization would be efficacious in aged mice with very advanced neuropathology. To address this issue, we immunostained sections with antibodies that recognize specific phospho-tau epitopes (AT100, AT8, PHF-1) or histologically evaluated sections following staining with Gallyas silver impregnation. As expected, neither active nor passive immunization had any discernable effect on the number of Gallyas-positive neurons or on the number of PHF-1- and AT8-positive neurons (Fig. 3, A-L). In contrast, we found that the number of AT100-positive neurons was reduced following immunization compared with the control groups (Fig. 3, M-P). This finding was notable as AT100 is an early marker of tau pathology in the 3xTg-AD mice, 4S. Oddo, A. Caccamo, and F. M. LaFerla, submitted manuscript. whereas AT8- and PHF-1-positive neurons appear at later ages (31Oddo S. Caccamo A. Shepherd J.D. Murphy M.P. Golde T.E. Kayed R. Metherate R. Mattson M.P. Akbari Y. LaFerla F.M. Neuron. 2003; 39: 409-421Abstract Full Text Full Text PDF PubMed Scopus (3196) Google Scholar). This finding is also consistent with our previous observations and the emerging data from the human clinical trials showing that soluble tau levels may be reduced by Aβ immunotherapy, whereas the NFT burden appears unchanged (32Ferrer I. Boada Rovira M. Sanchez Guerra M.L. Rey M.J. Costa-Jussa F. Brain Pathol. 2004; 14: 11-20Crossref PubMed Scopus (530) Google Scholar, 33Masliah E. Hansen L. Adame A. Crews L. Bard F. Lee C. Seubert P. Games D. Kirby L. Schenk D. Neurology. 2005; 64: 129-131Crossref PubMed Scopus (349) Google Scholar, 34Nicoll J.A. Wilkinson D. Holmes C. Steart P. Markham H. Weller R.O. Nat. Med. 2003; 9: 448-452Crossref PubMed Scopus (1294) Google Scholar). Although Gallyas-positive NFTs were unaffected by prolonged active or passive Aβ immunization, it is possible that soluble forms of tau may be reduced. To investigate this issue and to better quantify the changes in tau pathology, we measured total tau levels by Western blot using several phosphodependent (PHF-1, AT8, and AT100) tau antibodies. As expected based on the immunohistochemical data, we found that the levels of PHF-1 and AT8 reactivity were unaltered among all the groups (Fig. 4, A-C), whereas there was a significant reduction in AT100 levels in the immunized mice compared with the control groups (Fig. 4, A and D). To better quantify the changes in tau, we quantitatively measured tau levels in the soluble and insoluble fraction by sandwich ELISA and found that insoluble tau levels were unaltered among all the groups (Fig. 4E). Notably, soluble tau levels were significantly reduced in the actively and passively immunized mice compared with untreated or adjuvant-treated control mice (Fig. 4E). These results are consistent with our previous results showing that a single injection of an anti-Aβ antibody is sufficient to clear not only Aβ but also early tau pathology (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar, 30Oddo S. Caccamo A. Tran L. Lambert M.P. Glabe C.G. Klein W.L. LaFerla F.M. J. Biol. Chem. 2006; 281: 1599-1604Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar). The mechanism underlying the Aβ antibody-mediated reduction in tau pathology appears to be dependent on the proteasome, as inhibiting its activity prevented the Aβ-mediated clearance of tau (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar).FIGURE 4Soluble tau levels were reduced by both active and passive immunization. A, representative Western blots probed with a series of anti-tau antibodies. B and C, consistent with the immunohistochemical findings, the levels of PHF1 and AT8 by Western blot were unaltered following active and passive immunization, whereas the levels of AT100 immunoreactivity (D) was significantly reduced following both active and passive immunization. Note that densitometric analyses were performed by normalizing PHF-1, AT8, and AT100 levels to β-actin. E, sandwich ELISA measurements revealed that the levels of detergent-insoluble tau were unaffected by Aβ immunotherapy, whereas the levels of detergent-soluble tau were significantly reduced in the immunized mice versus untreated and adjuvant-treated 3xTg-AD mice.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Reducing Soluble Aβ without Reducing Soluble Tau Does Not Improve Cognition—Taken together, the data presented here demonstrate that it is possible to ameliorate the cognitive impairments in the 3xTg-AD mice by reducing soluble Aβ42 and tau levels, even in the presence of thioflavine-positive plaques and Gallyas-positive NFTs. It remains to be established, however, if the reduction of both soluble Aβ42 and tau levels is necessary to rescue the cognitive impairments or if the reduction of only soluble Aβ42 will suffice. We previously showed that the clearance of Aβ and tau pathology is hierarchical, with Aβ pathology cleared first and tau pathology reduced following the clearance of Aβ pathology (19Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar). Moreover, recent data indicate that a single intraperitoneal injection of a monoclonal Aβ antibody is sufficient to rescue the behavioral deficit" @default.
• W2075725519 created "2016-06-24" @default.
• W2075725519 creator A5008959840 @default.
• W2075725519 creator A5009317100 @default.
• W2075725519 creator A5011242018 @default.
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• W2075725519 date "2006-12-01" @default.
• W2075725519 modified "2023-10-16" @default.
• W2075725519 title "Reduction of Soluble Aβ and Tau, but Not Soluble Aβ Alone, Ameliorates Cognitive Decline in Transgenic Mice with Plaques and Tangles" @default.
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