Journal
STEM CELLS AND DEVELOPMENT
Volume 17, Issue 3, Pages 423-439Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/scd.2008.0018
Keywords
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Funding
- NIA NIH HHS [K99 AG029726-01, K99 AG029726, R00 AG029726-02, R41AG031586, R01 AG032432, R00 AG029726] Funding Source: Medline
- NINDS NIH HHS [R01NS048335] Funding Source: Medline
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Modulation of immune/inflammatory responses by diverse strategies including amyloid-beta (A beta) 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 A beta levels/beta-amyloid plaques and associated astrocytosis following multiple low-dose infusions of HUCBCs. HUCBC infusions also reduced cerebral vascular A beta 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 A beta levels. Moreover, microglia isolated from HUCBC-infused PSAPP mice demonstrated increased phagocytosis of A beta. Furthermore, sera from HUCBC-infused PSAPP mice significantly increased microglial phagocytosis of the A beta(1-42) peptide while inhibiting interferon-gamma-induced 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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