Authors:
William V. Nikolic, Huayan Hou, Terrence Town, Yuyan Zhu,
Brian Giunta, Cyndy D. Sanberg, Jin Zeng, Deyan Luo, Jared Ehrhart,
Takashi Mori, Paul R. Sanberg, and Jun Tan
Summary:
Modulation of immune/inflammatory responses by diverse strategies including amyloid-_ (A_) 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_ levels/_-amyloid plaques
and associated astrocytosis following multiple low-dose infusions of HUCBCs. HUCBC infusions also reduced cerebral vascular A_ 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_ levels. Moreover, microglia isolated from HUCBC-infused PSAPP mice demonstrated increased phagocytosis of A_. Furthermore, sera from HUCBC-infused PSAPP mice significantly increased microglial phagocytosis of the A_1-42 peptide while inhibiting interferon-_-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.
Source:
Stem Cells and Development 17:1–17 (2008).