Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Chuanhai Cao, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Bi Zhao, Ph.D.

Keywords

Aggregation, Neurodegenerative Diseases, Neuroprotection, Peptidemimic

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and progressive neuronal degeneration. Despite extensive research, no treatments have been able to effectively halt or reverse the progression of the disease. This study aimed to evaluate the therapeutic potential of two novel γ-AApeptides, HW-C9 and 125-6b, in AD treatment, assessing both their individual and combined effects. HW-C9 was designed to inhibit Aβ aggregation, while 125-6b was developed to promote neuronal growth and repair. Initially, the therapeutic effects of HW-C9 and 125-6b were assessed both in vitro and in vivo. The results showed that HW-C9 effectively inhibited Aβ aggregation and did not exhibit significant cytotoxicity in biochemical assays, while 125-6b promoted neuronal growth and enhanced neuronal survival. Subsequently, the combined treatment of HW-C9 and 125-6b was tested in an AD model. Aged human APP transgenic mice were administered the combined peptide therapy intranasally for three months. Cognitive function was evaluated using the Radial Arm Water Maze (RAWM), which demonstrated improvements in memory. Our findings suggest that the combination of HW-C9 and 125-6b has a synergistic effect, effectively inhibiting Aβ aggregation while promoting neuronal growth. These results support the potential of multifunctional treatment strategies for AD, offering both neuroprotective and neuroregenerative effects.

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