Novel Piperazine Based Compounds Target Alzheimer’s Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein

• Published in: ACS chemical neuroscience 2024-11, Vol.15 (21), p.3901-3914
• Main Authors: Armstrong, Christopher, Luo, Dan, Gretzinger, Anna, Pandey, Deepti, Lipchik, Andrew, Todi, Sokol V., Dutta, Aloke K.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Animals; Animals, Genetically Modified; Drosophila melanogaster; Humans; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Piperazine - chemistry; Piperazine - pharmacology; Piperazines - pharmacology; tau Proteins - metabolism
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00220

Alzheimer’s disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1–42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1–42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1–42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.