Peripherally Administered Human Umbilical Cord Blood Cells Reduce Parenchymal and Vascular β -Amyloid Deposits in Alzheimer Mice

Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
Stem Cells and Development (Impact Factor: 3.73). 07/2008; 17(3):423-39. DOI: 10.1089/scd.2008.0018
Source: PubMed

ABSTRACT Modulation of immune/inflammatory responses by diverse strategies including amyloid-beta (Abeta) immunization, nonsteroidal anti-inflammatory drugs, and manipulation of microglial activation states has been shown to reduce Alzheimer's disease (AD)-like pathology and cognitive deficits in AD transgenic mouse models. Human umbilical cord blood cells (HUCBCs) have unique immunomodulatory potential. We wished to test whether these cells might alter AD-like pathology after infusion into the PSAPP mouse model of AD. Here, we report a marked reduction in Abeta levels/beta-amyloid plaques and associated astrocytosis following multiple low-dose infusions of HUCBCs. HUCBC infusions also reduced cerebral vascular Abeta deposits in the Tg2576 AD mouse model. Interestingly, these effects were associated with suppression of the CD40-CD40L interaction, as evidenced by decreased circulating and brain soluble CD40L (sCD40L), elevated systemic immunoglobulin M (IgM) levels, attenuated CD40L-induced inflammatory responses, and reduced surface expression of CD40 on microglia. Importantly, deficiency in CD40 abolishes the effect of HUCBCs on elevated plasma Abeta levels. Moreover, microglia isolated from HUCBC-infused PSAPP mice demonstrated increased phagocytosis of Abeta. Furthermore, sera from HUCBC-infused PSAPP mice significantly increased microglial phagocytosis of the Abeta1-42 peptide while inhibiting interferon-gammainduced microglial CD40 expression. Increased microglial phagocytic activity in this scenario was inhibited by addition of recombinant CD40L protein. These data suggest that HUCBC infusion mitigates AD-like pathology by disrupting CD40L activity.

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Available from: Paul Sanberg, Sep 26, 2015
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    • "HUCBCs induce strong immunomodulatory properties by the host and yet remain weakly immunogenic themselves (Vendrame et al., 2006; Nikolic et al., 2008). As observed in an animal stroke model, HUCBCs inhibit the pro-inflammatory T helper cell type 1 (Th1) response, while promoting a strong anti-inflammatory T helper 2 (Th2) response (Vendrame et al., 2004; Nikolic et al., 2008). Numerous studies having shown that HUCBC treatment of rodents does not elicit GVHD (Graft Versus Host Disease), a leading cause of death in patients that have received stem cell transplants (Li et al., 2001b; Lu et al., 2002; Henning et al., 2004; Hu et al., 2006). "
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    Frontiers in Human Neuroscience 06/2014; 8:382. DOI:10.3389/fnhum.2014.00382 · 2.99 Impact Factor
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    • "Intravenously -reduced cerebral parenchymal and vascular A␤ plaques -decreased circulating and brain soluble CD40L -elevated systemic IgM levels -reduced CD40+ microglia and GFAP+ astrocytes -increased microglial phagocytosis of A␤ -increased plasma A␤ levels correlated with decreased CD40–CD40L interaction -not tested [97] NSCs 500,000 cells disomic and trisomic Ts65Dn mice Hippocampus unilaterally -reduced tau/reelin-positive granules in the Rad/LM of CA1 -not tested [98] "
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    Journal of Alzheimer's disease: JAD 08/2013; 37(2). DOI:10.3233/JAD-130572 · 4.15 Impact Factor
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    • "Although the method is widely used [4, 26, 59], the irradiation in the chimeric model has been legitimately criticized for causing preconditioning leading to increased permeability of BBB and excessive peripheral cell infiltration into the brain parenchyma [1, 2••]. Other approaches have been to transplant the cells to naive mouse circulation or locally into the brain to study their Aβ phagocytosis [28, 30•, 60]. "
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    ABSTRACT: Glial cells in Alzheimer's disease (AD) have been shown to be capable of clearing or at least restricting the accumulation of toxic amyloid beta (Aβ) deposits. Recently, bone marrow (BM)-derived monocytic cells have been recognized in experimental studies to be superior in their phagocytic properties when compared to their brain endogenous counterparts. In human AD, BM-derived monocytic cells may have deficiencies in their capacity to restrict plaque growth. Therefore, enhancement of phagocytic properties of cells of monocyte origin, both brain endogenous microglia and BM-derived monocytic cells, offers an attractive therapeutic approach to fight off AD. Transgenic mouse models with aberrant Aβ deposition offer a valuable tool for discovery of novel pathways to facilitate cell-mediated Aβ uptake. This article reviews the most recent findings on the phagocytic capacity of cells with monocytic origin in various transgenic AD models and describes the methods to study phagocytic activity of these cells.
    03/2012; 1(1):11-20. DOI:10.1007/s13670-011-0004-z
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