Evaluating the therapeutic effects of a peptide-based inhibitor of amyloid aggregation in mouse models of Alzheimer's disease

Ji, Hao (2024): Evaluating the therapeutic effects of a peptide-based inhibitor of amyloid aggregation in mouse models of Alzheimer's disease. Dissertation, LMU München: Medizinische Fakultät

Abstract

Alzheimer's disease (AD), a predominant neurodegenerative disorder, leads to cognitive impairment stemming from extensive neuronal loss with limited disease-modifying therapies (DMTs) available. Central to AD pathology is the accumulation of amyloid-beta (Aβ) peptide, a key player in disease progression. In addition to the Aβ-specific monoclonal antibodies, islet amyloid polypeptide (IAPP) has been found to attenuate amyloid self-assembly in vitro and in vivo. Building on IAPP's "cross-amyloid" inhibitor function, the macrocyclic 17-residue peptide 2E was designed as a mimic of the interaction surface of IAPP with Aβ. Encouragingly, 2E turned out to be a potent inhibitor with nanomolar affinity of Aβ amyloid self-assembly in vitro and, in addition, it exhibited significant proteolytic stability in human plasma and the ability to cross the blood-brain barrier (BBB) in a cell model. These favorable, drug-like, properties of 2E motivated us to test its effectiveness on amyloid pathology in AD mouse models. In my thesis, I investigated the efficacy of two treatment paradigms of the macrocyclic peptide 2E in ameliorating amyloid pathology using both female and male 5XFAD mice, a commonly used animal model for AD. The findings revealed a significant reduction in cortical amyloid deposition, decreased plasma and CSF Aβ42 concentration, increased Aβ40 levels, shifted amyloid deposition from brain parenchyma to blood vessels, decreased neuronal damage, and enhanced astrocytic activation upon 2E administration. Similar effects of 2E on soluble Aβ42 and Aβ40 changes were observed in APPNL-G-F transgenic mice. Furthermore, treated 5XFAD mice displayed improvements in memory and motor functions without any alterations in anxiety or stress responses, as evidenced by various behavioral tests. Notably, I established a novel method to perform high-resolution RNA sequencing from PFA-fixed microscopy slices. RNA-seq analyses highlighted 2E's ability to bolster astrocytic activation while reversing AD-associated neuronal gene expression changes. Importantly, following intraperitoneal (i.p.) injection, 2E's presence in the brain attests to its biodistribution capability. Thus, the macrocyclic peptide 2E, either as a standalone or combined with other anti-amyloid strategies, emerges as a promising drug candidate to combat Aβ-driven AD pathogenesis.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. Juli 2024
• 1. Bericht­erstatter:in: Bernhagen, Jürgen