| First Author | Habib A | Year | 2018 |
| Journal | Cell Transplant | Volume | 27 |
| Issue | 3 | Pages | 438-455 |
| PubMed ID | 29560732 | Mgi Jnum | J:368279 |
| Mgi Id | MGI:6269121 | Doi | 10.1177/0963689718759473 |
| Citation | Habib A, et al. (2018) Human Umbilical Cord Blood Serum-derived alpha-Secretase: Functional Testing in Alzheimer's Disease Mouse Models. Cell Transplant 27(3):438-455 |
| abstractText | Alzheimer's disease (AD) is an age-related disorder that affects cognition. Our previous studies showed that the neuroprotective fragment of amyloid procurer protein (APP) metabolite, soluble APPalpha (sAPPalpha), interferes with beta-site APP-cleaving enzyme 1 (BACE1, beta-secretase) cleavage and reduces amyloid-beta (Abeta) generation. In an attempt to identify approaches to restore sAPPalpha levels, we found that human cord blood serum (CBS) significantly promotes sAPPalpha production compared with adult blood serum (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells stably expressing wild-type human APP. Interestingly, CBS selectively mediated the alpha-secretase cleavage of human neuron-specific recombinant APP695 in a cell-free system independent of tumor necrosis factor-alpha converting enzyme (TACE; a disintegrin and metalloproteinase domain-containing protein 17 [ADAM17]) and ADAM. Subsequently, using 3-step chromatographic separation techniques (i.e., diethylaminoethanol, size-exclusion, and ion-exchange chromatography), we purified and ultimately identified a CBS-specific fraction with enhanced alpha-secretase catalytic activity (termed alphaCBSF) and found that alphaCBSF has more than 3,000-fold increased alpha-secretase catalytic activity compared with the original pooled CBS. Furthermore, intracerebroventricular injection of alphaCBSF markedly increased cerebral sAPPalpha levels together with significant decreases in cerebral Abeta production and abnormal tau (Thr(231)) phosphorylation compared with the AgBS fraction with enhanced alpha-secretase activity (AgBSF) treatment in triple transgenic Alzheimer's disease (3xTg-AD) mice. Moreover, AgBSF administered intraperitoneally to transgenic mice with five familial Alzheimer's disease mutations (5XFAD) via an osmotic mini pump for 6 weeks (wk) ameliorated beta-amyloid plaques and reversed cognitive impairment measures. Together, our results propose the necessity for further study aimed at identification and characterization of alpha-secretase in CBS for novel and effective AD therapy. |
