Abeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice.

Biomedical Sciences, University of California Riverside, 92521-0121, USA.
Neurobiology of Disease (Impact Factor: 5.08). 09/2006; 23(2):351-61. DOI: 10.1016/j.nbd.2006.03.008
Source: PubMed


Active and passive Abeta immunotherapy provide behavioral benefits in AD transgenic mice, but they can also induce adverse immune over-activation and neuropathological effects. Here, we show that a restricted Abeta-specific immune re-activation can provide cognitive and pathological benefits to APPsw + PS1 transgenic mice for at least 2 1/2 months. A single infusion of Abeta-specific immune cells from Abeta-vaccinated littermates improved performance in cognitively impaired APP + PS1 mice. Recipients had lower levels of soluble Abeta in the hippocampus, less plaque-associated microglia, and more intense synaptophysin immunoreactivity, compared with untreated controls. However, Abeta-specific infusates enriched for Th1 or depleted of CD4(+) T-cells were not effective, nor were ovalbumin-specific infusates. These benefits occurred without global or brain-specific inflammatory responses. Chronically high levels of Abeta can cause immune tolerance, hypo-responsiveness, or anergy to Abeta, but our findings demonstrate that Abeta-specific immune cells can resume endogenous Abeta-lowering processes and may be an effective Abeta therapeutic.

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Available from: Chuanhai Cao, Sep 09, 2014
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    • "Immune cells such as dendritic-like microglia, macrophages in CNS, and peripheral T cells, along with cytokines, maintain the proper microenvironment in brains and prevent the development of neurodegenerative diseases by clearing cerebral metabolites and deleterious substances (Cao et al., 2009; Hawkes and McLaurin, 2009; Kipnis et al., 2004; Moalem et al., 1999; Rolls et al., 2007; Ron-Harel et al., 2008; Simard et al., 2006). As Alzheimer's disease (AD) is one kind of neurodegenerative diseases, immunotherapy against AD have been extensively explored in recent years (Cao et al., 2009; Ethell et al., 2006; Fisher et al., 2010; Fuhrmann et al., 2010; Kummer et al., 2012). "
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    ABSTRACT: Anti-amyloid-β (Aβ) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aβ immunotherapy. In this study, a combined treatment of Aβ1-42-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aβ antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aβ plaques. In conclusion, the Aβ1-42-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.
    Neurobiology of Aging 07/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.06.029 · 5.01 Impact Factor
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    • "After PDFM was selected as the optimal peptide for use in our DC vaccine, 9.5-month old Tg-APP+PS1 mice (n = 18) mice and aged matched C57BL/6 non-Tg mice (n = 6) were obtained from the USF Health Byrd Alzheimer Institute. The APP+PS1 mice were produced from a cross between mutant APPK670N,M671L Tg line Tg 2576 and mutant PS1 Tg line and were of mixed background (C57 = 28%, B6 = 58%, SW = 6%, SJL = 8%) [32]. After determination of the optimal peptide for DC vaccine preparation, the Tg mice were randomly divided into 3 groups: the Tg PDFM, Tg-PWT, and the Tg Control groups. "
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    ABSTRACT: Previously, our lab was the first to report the use of antigen-sensitized dendritic cells as a vaccine against Alzheimer's disease (AD). In preparation of this vaccine, we sensitized the isolated dendritic cells ex vivo with Aβ peptide, and administered these sensitized dendritic cells as a therapeutic agent. This form of cell therapy has had success in preventing and/or slowing the rate of cognitive decline when administered prior to the appearance of Aβ plaques in PDAPP mice, but has not been tested in 2×Tg models. Herein, we test the efficacy and safety of this vaccine in halting and reversing Alzheimer's pathology in 9-month-old APP+PS1 mice. The results showed that administration of this vaccine elicits a long-lasting antibody titer, which correlated well with a reduction of Aβ burden upon histological analysis. Cognitive function in transgenic responders to the vaccine was rescued to levels similar to those found in non-transgenic mice, indicating that the vaccine is capable of providing therapeutic benefit in APP+PS1 mice when administered after the onset of AD pathology. The vaccine also shows indications of circumventing past safety problems observed in AD immunotherapy, as Th1 pro-inflammatory cytokines were not elevated after long-term vaccine administration. Moreover, microhemorrhaging and T-cell infiltration into the brain are not observed in any of the treated subjects. All in all, this vaccine has many advantages over contemporary vaccines against Alzheimer's disease, and may lead to a viable treatment for the disease in the future.
    PLoS ONE 12/2012; 7(12):e49468. DOI:10.1371/journal.pone.0049468 · 3.23 Impact Factor
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    • "Although G-CSF administration in normal older donors is not common, safety reviews demonstrate equal tolerance and transient side-effect profile as in younger donors. The yield of collected stem cells from older donors (>55) has been reported to be poor [28], although age has not been found to be a significant or major predictive factor of stem cell yield in other studies [29]. Up to the present, there have been no studies of G-CSF administration to patients with AD. "
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    ABSTRACT: Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance.
    Journal of Alzheimer's disease: JAD 06/2012; 31(4):843-55. DOI:10.3233/JAD-2012-120196 · 4.15 Impact Factor
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