Graduation Year
2019
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Medical Sciences
Major Professor
Jun Tan, M.D., Ph.D.
Committee Member
Thomas Taylor-Clark, Ph.D.
Committee Member
Brian Giunta, M.D., Ph.D.
Committee Member
Jaya Padmanabhan, Ph.D.
Committee Member
Kevin Nash, Ph.D.
Keywords
Alzheimer's Disease, Complement, Cord blood serum, LISPRO, Lithium, HUCBS
Abstract
Dementia is the top global public health threat of the twenty first century. Within the dementia spectrum, Alzheimer’s disease (AD) is the most common type of dementia that occurs with aging and accounts for about 60% - 80% of diagnosed cases. But currently available discoveries failed to develop disease-modifying therapies for all patients living with AD. Recent discoveries can only partially slow down cognitive decline in a small subset of patients with limited effectiveness. The heterogeneity and complexity of the pathophysiology of AD indicate that a single drug approach may not be sufficient to prevent disease onset and progression. Human umbilical cord blood cells (HUCBC) and lithium treatment have shown promise against numerous neurological conditions, including AD. Yet, they also show significant unwanted, adverse effects. To address this barrier to yield successful treatments, we employed two key modifications to these two treatment strategy. We used human umbilical cord blood derived serum (HUCBS, also labeled as CBS) rather than HUCBC. We also utilized ionic cocrystal of lithium salicylate l-proline (LISPRO, also labeled as LP) instead of usual lithium salt. Both HUCBS and LISPRO have been shown to have strong neuroprotective, anti-inflammatory properties in separate studies conducted in transgenic AD mouse models. The studies detailed herein independently investigated the effectiveness of biological (HUCBS) and pharmacological (LISPRO) approaches in modulating the pathology and cognitive impairments in AD mouse models (e.g., 5XFAD, 3XTg-AD, APPswe/PS1dE9, and Tg2576).
While administration of HUCBC stimulate anti-inflammatory pathways shown in previous studies, we found that HUCBS markedly promoted neurotrophic soluble amyloid precursor protein alpha (sAPPα) through non-amyloidogenic amyloid precursor protein (APP) processing pathway compared to adult (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells expressing wild type APP (CHO/APPwt). Using chromatographic fractionation, mass-spectrometry, and targeting complement proteins in cord blood serum fraction (αCBSF), we discovered the source of sAPPα in HUCBS as C1 complement protein. Further, intraperitoneal administration of αCBSF via osmotic minipump for 6 weeks showed prevention of cognitive impairment in 5XFAD mice assessed by novel object recognition, and Y-maze test.
A series of recent studies have shown that lithium can prevent both AD- and age-associated cognitive decline. But, current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate forms) have a narrow therapeutic window and unstable pharmaceutics that can cause toxicity without monitoring. Here we investigated the safety, pharmacokinetics, and therapeutic efficacy of LISPRO (LP), lithium salicylate (LS), and lithium carbonate (LC) in cell culture and mouse (B6129SF2/J, Tg2576, and 3xTg-AD) models. Cytokine profiles from the brain, plasma and splenocytes demonstrated that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines and suppress renal cyclooxygenase 2 (COX2) expression in Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain and more steady plasma lithium levels in both B6129SF2/J and transgenic Tg2576 mice compared with lithium carbonate. Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Moreover, female APPswe/PS1dE9 mice at 4 months of age were orally treated with LP, LS, or LC for 8- to 9- months at 2.25 mmol lithium/kg/day followed by measuring body weight, internal organs’ growth, and cognitive and non-cognitive function. LISPRO treatment prevented cognitive decline compared with transgenic APPswe/PS1dE9 cohort, as shown by shorter escape latency during training and probe trials in the Morris water maze and longer contextual freezing time during fear conditioning. As expected, LISPRO treatment also reduced depression assayed by tail suspension test and irritability assessed with the touch escape test. But, lithium treatment did not alter anxiety or locomotor activity as assessed by open field, elevated plus maze or accelerated rotarod tests.
Taken together, these data indicate that both biological HUCBS and pharmacological LISPRO treatment may prove to be viable effective strategy for ameliorating Alzheimer’s like pathology and cognitive impairment in preclinical models.
Scholar Commons Citation
Habib, Md Ahsan, "Therapeutic modulation of Alzheimer’s disease with biological (HUCBS) and pharmacological (LISPRO) approaches" (2018). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/7678
