Novel Multitarget Directed Tacrine Hybrids as Anti-Alzheimer’s Compounds Improved Synaptic Plasticity and Cognitive Impairment in APP/PS1 Transgenic Mice

Abstract

Alzheimer’s disease (AD) is a complex pathological neurodegenerative disease that seriously threatens human health. Therefore, how to effectively improve and treat AD is an urgent problem. In this study, a novel multitarget derivative based on tacrine (named 9i), which could work simultaneously on more than one pathological target, was used to treat AD model APP/PS1 transgenic mice. After 4 weeks of intragastric administration, cognitive function and synaptic plasticity were significantly improved and β-amyloid (Aβ) plaques that are main pathological hallmarks of AD were decreased in the APP/PS1 mice. On the one hand, 9i inhibited the excessive activation of the Raf/MEK/ERK signaling pathway to alleviate the loss of neurons, which provides a foundation for structural integrity. On the other hand, synaptic associated proteins and the density of synaptic spines were increased in APP/PS1 mice treated with 9i, which provides the basis for the improvement of synaptic plasticity and cognitive impairment. Interestingly, 9i also reduced Aβ plaques in the DG region, which is consistent with previous in vitro experiments showing that 9i inhibited the self-assembly of Aβ fibers, thus protecting neurons from Aβ plaque neurotoxicity. Our results suggest that 9i as a novel compound can effectively improve the cognitive function and the pathological changes of AD in APP/PS1 transgenic mice.

Tacrine-Based Hybrids: Past, Present, and Future

“…Because the number of articles devoted to the development of analogues of THA is enormous, we structured the articles published in 2006–2022 [ 30 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 …”

“…In 2020, the same scientific group reported significant improvements in cognitive function in APP/PS1 transgenic mice treated with 165 [ 55 ]. After 4 weeks of intragastric administration of 165 (1.27 mg/100 g), cognitive function and synaptic plasticity were improved.…”

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

“…Despite Tacrine being withdrawn from the market owing to its hepatotoxicity, the drug appears to improve cognitive performance in an AD transgenic animal model. Tacrine also increased the levels of NMDA receptor subunits NMDAR2A, NMDAR2B, and the synaptic-associated proteins PSD-95 and SYP [ 168 ]. Donepezil together with cerebrolysin showed a synergistic and protective effect on plasticity, promoting a wider dendritic arborization in pyramidal neurons of the prefrontal cortex, dorsal hippocampus, nucleus accumbens, and dentate gyrus [ 169 ].…”

Novel Coumarin–Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer’s Disease

“…Advancement of multi-target-directed ligands (MTDLs) is one of the most encouraging drug discovery methods for ailments with a complex nature like AD. Mono-targeted medicines could not forever amend the complex ailing system sufficiently, even if these compounds regulate their targets with extreme selectivity and affinity ( Zhang et al, 2016 ; Alcaro et al, 2019 ; González et al, 2019 ; Li et al, 2020 ). MTDLs have a superior capability to exert influence on the complicated balance of entire cellular network than single-targeted drug due to their synchronous consequences on various curative targets.…”