Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide and causes progressive cognitive impairment and dementia. The main pathological features of AD include the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles, composed of amyloid beta (Aβ) peptides and hyperphosphorylated tau protein, respectively. Aβ peptides are derived from the proteolytic cleavage of amyloid precursor protein (APP), a transmembrane protein that is involved in various cellular functions. The aggregation and toxicity of Aβ peptides are influenced by several factors, such as oxidative stress, inflammation, metal ions, and genetic mutations. Among the metal ions, copper (Cu) has been implicated in AD pathogenesis due to its high affinity for Aβ peptides and its ability to catalyze the generation of reactive oxygen species. Cu is also an essential trace element functioning as a catalytical center of enzymes or a structural site of proteins that play vital roles in various biological processes, such as neurotransmission, energy metabolism, antioxidant defense, and gene expression. Cu dysregulation can lead to either Cu deficiency or Cu excess, both of which can have detrimental effects on brain function and health. High levels of copper in the brain can promote the formation of Ab plaques that is very likely to play a key role in the development and progression of AD. Other studies have suggested that copper may also contribute to the oxidative stress and inflammation that are associated with AD. At present, the relationship between copper and AD is complex and not fully understood.
In a new study published in the peer-reviewed Journal ACS Chemical Neuroscience, Dr. Fanfan Sun, Dr. Jie Zhao, Mr. Huajie Zhang, Miss. Qihui Shi, and Prof. Qiong Liu from Shenzhen University were in collaboration with Prof. Yan Liu, Prof. Anne Robert, and Prof. Bernard Meunier from Guangdong University of Technology and Laboratoire de Chimie de Coordination du CNRS investigated TDMQ20, a specific copper chelator that is designed to regulate copper homeostasis and inhibit the deleterious oxidative stress induced by copper-Aβ complexes. The researchers investigated the proteomic alterations in the cortex of 5xFAD mice (a mouse model of AD) after an oral treatment of TDMQ20 and compared them with those of clioquinol (CQ), a non-copper specific chelator. TDMQ20 was found to have beneficial effects on the cholinergic system and synaptic transmission in the cortex of 5xFAD mice.
TDMQ20 is a compound that has been studied for its potential use for the treatment of AD. It is thought to work in the brain by grabbing copper ions from amyloidal aggregates and transferring them to physiologically active copper enzymes, which are believed to play a key role in inhibiting the development and progression of AD pathology. While these results are promising, it’s important to note that TDMQ20 is still in the early stages of development as a clinical therapy for AD. More research is still needed to fully understand its potential benefits and any potential side effects or risks. The research team applied iTRAQ proteomics technology to explore the effects of TDMQ20 on the cortex of 5xFAD mice and the potential pathways it may involve in. The researchers found that 178 differentially expressed proteins (DEPs) were identified in the AD mouse group with respect to wild type (WT) animals (AD/WT), and that 35 DEPs were common in AD/WT and TDMQ20/AD categories with an opposite change manner (up- and down-regulated, respectively). The authors also found that 10 common target proteins were identified in AD/WT, TDMQ20/AD, and CQ/AD categories, and successfully validated 3 target proteins by Western blot analysis: ChAT, CHRM4, and Lgalsl. Further, the researchers found that TDMQ20 significantly increased the expression levels of ChAT and CHRM4, two key proteins involved in the cholinergic system in the brain, while CQ did not significantly change the expression levels of these proteins. According to the authors, TDMQ20 may modulate the cholinergic system and synaptic transmission by regulating copper homeostasis and inhibiting copper-Aβ complexes, and that TDMQ20 may improve cognitive and behavioral performance in AD mice by restoring the balance of neurotransmitters and synaptic plasticity. The authors concluded that TDMQ20 can modulate the expression levels of proteins related to the cholinergic system and synaptic transmission in 5xFAD mouse model.
Finding an effective therapy for AD is crucial for several reasons. Firstly, AD is a debilitating condition that affects millions of people worldwide, and there is currently no cure. The disease causes a gradual decline in cognitive function, memory loss, and ultimately results in a complete loss of independence and quality of life for those affected. Therefore, developing effective therapies can improve the quality of life for people living with the disease. Moreover, the search for an effective therapy for AD has implications for the field of neuroscience and medicine as a whole. The disease is complex, and understanding its underlying mechanisms could lead to new insights into other neurological conditions and provide opportunities for the development of new treatments. The study provided proteomics evidence for the role of TDMQ20 as a potential therapeutic agent for AD.
Sun F, Zhao J, Zhang H, Shi Q, Liu Y, Robert A, Liu Q, Meunier B. Proteomics evidence of the role of TDMQ20 in the cholinergic system and synaptic transmission in a mouse model of Alzheimer’s disease. ACS Chemical Neuroscience. 2022 ;13(21):3093-107.