Investigation of Aβ42 C-Terminal Fragments as Inhibitors of Aβ42 Assembly and Neurotoxicity

摘要

Alzheimer's disease (AD) is characterized by aging-associated deterioration of learning and memory leading to dementia. A key event in AD etiology is the assembly of amyloid P-protein (Aβ) into neurotoxic oligomers [1]. Two predominant forms of Aβ are produced in vivo, comprising 40 (Aβ40) or 42 (Aβ42) amino acid residues. Aβ42 has been shown to be more neurotoxic than Aβ40 [2]. Disruption of Aβ oligomerization is a promising approach for developing therapeutics for AD. We have prepared a series of Aβ42 C-terminal fragments (CTFs), evaluated their bioactivity, and identified lead inhibitors of Aβ42 assembly and neurotoxicity [3]. Of 12 CTFs tested (Table 1), Aβ(31-42) and Aβ(39-2) were found to be the most potent inhibitors of AP42-induced toxicity. To decipher the mechanisms by which CTFs affect Aβ assembly and neurotoxicity, we investigated the solubility, self-aggregation, secondary structure, morphology, and interaction with full-length Aβ42 of the CTFs and of 4 control, Aβ-derived fragments, including Ac- Aβ(1622)-NH2, Aβ(21-30), Aβ(30-40), and Aβ(34-40). The first two peptides are derived from Aβ regions that are involved in Aβ aggregation and nucleation, which enable to test if the inhibition of Aβ42-induced toxicity required CTF derived from Aβ42 itself or whether sequences derived from other regions also had inhibitory activity. The latter two peptides are CTFs derived from Aβ40. These fragments test the importance of the C-terminal dipeptide, I41-A42, in Aβ42 for the inhibitory activity.