Thesis (Ed.D)--Teachers College, Columbia University, 1991. / Typescript; issued also on microfilm. Sponsor: Patricia L. Munhall. Dissertation Committee: Elizabeth H. Tucker. Includes bibliographical references (p. 153-161).

Thesis (Ph. D.)--University of California, San Diego, 2000. / Vita. Includes bibliographical references.

Neuroinflammation occurs in Alzheimer’s disease (AD) brain, and plays a role in neurodegeneration. The main aim of this study was to determine how treatments with exogenous apolipoprotein E (ApoE2, E3 and E4 isoforms), a genetic risk factor for AD, affects the amyloid-β (Aβ) induced inflammatory response in vitro in astrocytes. Recombinant, lipid-free ApoE4 was found not to affect Aβ-induced inflammation in rat astrocytes, while ApoE2 showed a protective effect. Mouse cells expressing human ApoE isoforms, which have similar lipidation and modification to native human ApoE, showed ApoE4 promoting inflammation, and no ApoE2 protective effect upon Aβ treatment. A Protein/DNA array was used to screen 345 transcription factors in rat astrocytes treated with Aβ and/or ApoE isoforms, in order to determine which contribute to the observed ApoE2 protection. Some candidates were validated by Western Blot or EMSA and/or by inhibition or activation. The findings suggest ApoE isoforms differentially regulate Aβ-induced inflammation, and multiple signalling pathways are involved in the process.

Alzheimer's disease has become one of the most common diseases jeopardizing the health of the human being. The main pathological feature of AD is the accumulation of Aβ in the brain to form senile plaques. Therefore, it is of great significance to develop new and efficient drugs targeting at amyloid-β for the detection, diagnosis and therapeutics for Alzheimer's disease. Xanthohumol (Xn) naturally presents in hops (Humulus lupulus L). Studies have shown that it has anti-lipoperoxidative, anti-inflammatory, anti-proliferative activities, antiangiogenic and antioxidant effects, which further illustrates its potential therapeutic for AD. However, the bio-incompatibility and blood-brain barrier impermeability of Xanthohumol hindered it in vivo efficacy potential for treating Alzheimer's disease. Thus, we designed and prepared a series of Xanthohumol derivatives, namely, Xn-n, (n = 1-9) and its chalcone derivatives C-n, (n = 1-10) to enhance the desirable physical, biological and pharmacological properties, especially the blood-brain barrier permeability for intervention of AD. As an effective technique for in vivo visualization, Near-infrared fluorescence imaging based on organic small molecule probes has a promising application in the diagnosis of Alzheimer's disease. However, most of the reported imaging probes can only visualize Aβ-plaques but do not have therapeutic potential such as neuroprotection against Aβ induced toxicity. Herein, we designed and synthesized a series of oligomeric Aβ targeted near infrared (NIR) fluorescent probes for the diagnosis and therapeutics of Alzheimer's disease, namely DBAN-SLM, DBAN-SLOH, DBAN-OSLM which showed remarkably effective inhibitory effect on Aβ aggregation, significant neuroprotection effect against the Aβ-induced toxicities, and suppression on Aβ-induced ROS generation. indicating its great promise as a useful theragnostic agent for the early diagnosis and therapy of AD. Dual-modal imaging is an important approach to overcome the limitations of single imaging technology in the diagnosis of AD disease. Therefore, based on the dual-modal, we designed and synthesized the NIR/MR dual-modal detection and theragnostic probes namely Dyad-1, Dyad-2, Dyad-3 and NP@SiO2@F-SLOH. More surprising is that the two NIR/MR dual-modal probes show excellent biological properties, including the ability to inhibit Aβ aggregation to a certain extent, neuroprotective effects on cytotoxicity caused by different forms of Aβ species, blood-brain barrier (BBB) permeability, and high stability. All of these newly designed and synthesized molecules were characterized with 1H NMR, 13C NMR, and HRMS and found to show good agreement with the desired structures. The photophysical properties and biological properties of these novel designed and synthesized fluorescent probe such as UV-vis absorption, fluorescence emission, dissociation constant determined by fluorescence titration, cytotoxicity assay, neuroprotection, and inhibition of Aβ aggregation were investigated

Indiana University-Purdue University Indianapolis (IUPUI) / Neuroimaging biomarkers play a crucial role in our understanding of Alzheimer’s disease. Beyond providing a fast and accurate in vivo picture of the neuronal structure and biochemistry, these biomarkers make up a research framework, defined in a 2018 as the A(amyloid)/T(tau)/N(neurodegeneration) framework after three of the hallmarks of Alzheimer’s disease. I first used imaging measures of amyloid, tau and neurodegeneration to study clinically diagnosed Alzheimer’s disease. After dividing subjects into early (onset younger than 65) and late-onset (onset of 65 and older) amyloid-positive (AD) and amyloid-negative (nonAD) groups, I saw radically differing topographical distribution of tau and neurodegeneration. AD subjects with an early disease onset had a much more severe amyloid, tau and neurodegeneration than lateonset AD. In the nonAD group, neurodegeneration was found only in early-onset FDG PET data and in a nonAlzheimer’s-like MRI and FDG pattern for late-onset. The late-onset nonAD resembled that of limbic-predominant age-related TDP-43 encephalopathy. I next utilized an imaging genetics approach to associate genome-wide significant Alzheimer’s risk variants to structural (MRI), metabolic (FDG PET) and tau (tau PET) imaging biomarkers. Linear regression was used to select variants for each of the models and included a pooled sample, cognitively normal, mild cognitive impairment and dementia groups in order to fully capture the cognitive spectrum from normal cognition to the most severely impaired. Model selected variants were replicated using voxelwise regression in an exploratory analysis of spatial associations for each modality. For each imaging type, I replicated some associations to the biomarkers previously seen, as well as identified several novel associations. Several variants identified with crucial Alzheimer’s biomarkers may be potential future targets for drug interventions.

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published_or_final_version / Anatomy / Master / Master of Medical Sciences

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