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 APPα (sAPPα), interferes with β-site APP-cleaving enzyme 1 (BACE1, β-secretase) cleavage and reduces amyloid-β (Aβ) generation. In an attempt to identify approaches to restore sAPPα levels, we found that human cord blood serum (CBS) significantly promotes sAPPα 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 α-secretase cleavage of human neuron-specific recombinant APP695 in a cell-free system independent of tumor necrosis factor-α 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 α-secretase catalytic activity (termed αCBSF) and found that αCBSF has more than 3,000-fold increased α-secretase catalytic activity compared with the original pooled CBS. Furthermore, intracerebroventricular injection of αCBSF markedly increased cerebral sAPPα levels together with significant decreases in cerebral Aβ production and abnormal tau (Thr231) phosphorylation compared with the AgBS fraction with enhanced α-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 β-amyloid plaques and reversed cognitive impairment measures. Together, our results propose the necessity for further study aimed at identification and characterization of α-secretase in CBS for novel and effective AD therapy.

Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein (APP) is cleaved by α-secretase, generating soluble α-amyloid precursor protein (sAPPα), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-β-peptide (Aβ) of either 40 or 42 residues are generated by increased activity of β- and γ-secretase. These proteins amalgamate in specific regions of the brain, which disrupts neuronal functions and leads to cognitive impairment. Human umbilical cord blood cells (HUCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases, including AD. Our most recent work studied the impact of umbilical cord blood serum (CBS) on modulation of sAPPα production. Heat-sensitive CBS significantly promoted sAPPα production, indicating that heat-sensitive factor(s) play(s) a role in this process. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to determine the molecular source of α-secretase in purified CBS and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of C1 complex (C1q, C1r, and C1s) and alpha-2-macroglobulin showed significantly greater levels in purified α-CBS fraction (α-CBSF) compared with the AgBS fraction (AgBSF). Specifically, C1 markedly increased sAPPα and alpha-carboxyl-terminal fragment (α-CTF) production in a dose-dependent fashion, whereas C1q alone only minimally increased and C3 did not increase sAPPα production in the absence of sera. Furthermore, C1q markedly increased sAPPα and α-CTF, while decreasing Aβ, in CHO/APPwt cells cultured in the presence of whole sera. These results confirm our initial assumption that APP α-secretase activity in human blood serum is mediated by complement C1, opening a potential therapeutic modality for the future of AD.