Human umbilical cord blood cells (HUCBC) are well known specific immunomodutators that confer a balanced (i.e. without complete immunosuppression, GVHD, or rejection) alteration of both peripheral and central immune responses. Other investigators have demonstrated they promote mobilization of adult bone marrow (BM) progenitor cells. In addition we recently demonstrated sera derived from HUCBC-infused PSAPP mice significantly inhibited microglial CD40 expression induced by IFN-? and markedly increased microglial A? phagocytic activity without unacceptable immune compromise. In confirmation, this effect was inhibited by the ligation of CD40 with CD40L protein. Importantly, primary adult microglia from these HUCBC-infused mice also showed increased A? phagocytic activity, and a strong A? IgG titer. Together these data suggest a balanced alteration of both innate and humoral immune microenvironments mediated by an HUCBC induced suppression of CD40 signaling and enhancement of A? IgG production. In accord with this downregulation of neurotoxic innate responses and upregulation of salutary humoral responses, A? levels/?- amyloid deposits and cerebral amyloid angiopathy (CAA;an inflammatory response to vascular amyloid deposits) are reduced by HUCBC infusion in vivo, with attendant: (a) increased serum levels of A?1-40, 42, suggesting efflux from the CNS (b) decreased soluble CD40L serum levels, (c) decreased microglial CD40 expression, and finally, (d) elevated CNS/serum levels of anti-inflammatory (IL-10 and TGF-21) with decrease pro-inflammatory cytokines (IL-1? and TNF-a). Finally, our preliminary data suggests that, compared with control primary BM derived monocytes/macrophages (MO/X), MO/X from HUCBC-infused PSAPP mice show enhanced A? phagocytic activity. These data along with our previous findings that crossing Tg2576 mice with CD40L null mice or treating PSAPP mice with CD40L antibody reduced A? loads, lead us to hypothesize that HUCBC infusion confers a mitigation of A?/?-amyloid pathology in Alzheimer's disease (AD) mice by alterations in innate and humoral immunity mediated by CD40-CD40L disruption resulting in mobilization of BM-derived progenitor MO/X, increased anti-inflammatory cytokine production, and increased amyloid clearance from the brain. Here we propose to test the hypothesis that HUCBC mediated dampening of the CD40-CD40L interaction reduces amyloidosis by investigating CD40 signaling in HUCBC infused PSAPP mice. Based on our preliminary data, we additionally plan to reconstitute the effects of HUCBC infusion by administering IL- 10, TGF-?1 and NGF-? alone and in combinations;key factors we found to be essential for HUCBC ability to modulate CD40 activity and amyloidosis without systemic immunosuppression, rejection, or GVHD. Also, we will test the hypothesis that HUCBC infusion mobilizes BM-derived MO/X, leading to transdifferentiation into macrophages which enter the CNS and further differentiate into microglia with enhanced A? phagocytic capacity. It is our long-term goal to move this combination treatment into phase I human trials for patients with mild to moderate AD.
In the past years, we have shown that disruption of signaling through the CD40-CD40L system reduces amyloid deposition in the brains of APP (amyloid precursor protein) overproducing transgenic mice while ameliorating cognitive deficits. The CD40 blockade acts by slowing maturation of activated microglia thereby maintaining a phagocytic phenotype with concurrent decreased production of potentially neurotoxic cytokines (IL-?2 and TNF-?), and increased production of therapeutic anti-inflammatory cytokines (IL-10 and TGF-21) in the CNS. Most importantly this we demonstrated this phagocytic microglial phenotype enhances clearance of amyloid plaques from the brain parenchyma. Unfortunately CD40 blockade carries with it unacceptable immune-depleting side effects which makes this strategy less than optimal for transfer to the clinical setting. Human umbilical cord blood cells (HUCBC) are well known specific immunomodutators that confer a balanced alteration of peripheral and central, innate and humoral immune responses without rejection or systemic immunosuppression. In support, our preliminary data showed that CD40 expression and its signaling functions in peripheral antigen presenting cells (APCs) from HUCBC-infused mice are not affected, while those in the CNS experience increased phagocytic activity, down regulation of toxic cytokines, and increased generation of anti-inflammatory cytokines. Thus, this application proposes to investigate the hypothesis that HUCBC mediated dampening of the CD40-CD40L interaction reduces amyloidosis by investigating CD40 signaling in HUCBC infused PSAPP mice. Furthermore, we plan to investigate the soluble factors, including IL-10, TGF-?1 and NGF-? (these factors significantly elevated in HUCBC-infused mice), which modulate the CD40-CD40L interaction and reduced amyloid parenchymal load in this context with the long term goal of developing a combination treatment for use in human trials. Finally, the contribution of bone marrow-derived MO/X after HUCBC infusion into PSAPP mice will be determined. In summary, the expected results will suggest that HUCBC or, isolated soluble factors that HUCBC induce, would be a novel therapeutic strategy for AD.
|Habib, Ahsan; Sawmiller, Darrell; Tan, Jun (2016) Restoring Soluble Amyloid Precursor Protein Î± Functions as a Potential Treatment for Alzheimer's Disease. J Neurosci Res :|
|Darlington, Donna; Li, Song; Hou, Huayan et al. (2015) Human umbilical cord blood-derived monocytes improve cognitive deficits and reduce amyloid-Î² pathology in PSAPP mice. Cell Transplant 24:2237-50|
|Li, Song; Hou, Huayan; Mori, Takashi et al. (2015) Swedish mutant APP-based BACE1 binding site peptide reduces APP Î²-cleavage and cerebral AÎ² levels in Alzheimer's mice. Sci Rep 5:11322|
|Deng, Juan; Habib, Ahsan; Obregon, Demian F et al. (2015) Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3Î² signaling pathway. J Neurochem 135:630-7|
|Li, S; Deng, J; Hou, H et al. (2014) Specific antibody binding to the APP672-699 region shifts APP processing from Î±- to Î²-cleavage. Cell Death Dis 5:e1374|
|Smith, Adam J; Kim, Seol-Hee; Tan, Jun et al. (2014) Plasma and Brain Pharmacokinetics of Previously Unexplored Lithium Salts. RSC Adv 4:12362-12365|
|Zhang, She-Qing; Obregon, Demian; Ehrhart, Jared et al. (2013) Baicalein reduces Î²-amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer's disease transgenic mouse model. J Neurosci Res 91:1239-46|
|Mori, Takashi; Koyama, Naoki; Guillot-Sestier, Marie-Victoire et al. (2013) Ferulic acid is a nutraceutical Î²-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice. PLoS One 8:e55774|
|Darlington, Donna; Deng, Juan; Giunta, Brian et al. (2013) Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-Î²-associated neuropathology in Alzheimer mice. Stem Cells Dev 22:412-21|
|Hernandez-Ontiveros, Diana G; Tajiri, Naoki; Acosta, Sandra et al. (2013) Microglia activation as a biomarker for traumatic brain injury. Front Neurol 4:30|
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