Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice.
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.
Nikolic
William V
WV
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
Hou
Huayan
H
Town
Terrence
T
Zhu
Yuyan
Y
Giunta
Brian
B
Sanberg
Cyndy D
CD
Zeng
Jin
J
Luo
Deyan
D
Ehrhart
Jared
J
Mori
Takashi
T
Sanberg
Paul R
PR
Tan
Jun
J
D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001808:Blood Vessels / Q000473:pathology*; D001921:Brain / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002452:Cell Count; D064987:Cell- and Tissue-Based Therapy; D005312:Fetal Blood / Q000166:cytology* / Q000637:transplantation*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D010455:Peptides / Q000276:immunology; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D005904:Glial Fibrillary Acidic Protein; D010455:Peptides; D023201:CD40 Ligand