Abstract
Alzheimer’s disease (AD) is a progressive and age-related neurodegenerative disorder affecting brain cells and is the most common form of “dementia”, because of the cognitive detriment which takes place. Neuronal disruption represents its major feature, due to the cytosolic accumulation of amyloid β-peptide (Aβ) which leads to senile plaques formation and intracellular neurofibrillary tangles. Many studies have focused on the design and therapeutic use of new molecules able to inhibit Aβ aggregation. In this context, we evaluated the ability of two recently synthesized series of N-alkyl carbazole derivatives to increase the Aβ soluble forms, through molecular docking simulations and in vitro experiments. Our data evidenced that two carbazole derivatives, the most active, adopt distinct binding modes involving key residues for Aβ fibrillization. They exhibit a good interfering activity on Aβ aggregation in mouse (N2a) cells, stably expressing wild-type human amyloid precursor protein (APP) 695. These preliminary results are promising and we are confident that the N-alkyl carbazole derivatives may encourage next future studies needed for enlarging the knowledge about the AD disease approach.
Highlights
Alzheimer’s disease (AD) is an age-related disorder that affects brain cells, leads to the inability to conduct a normal life and because of the chronic and progressive cognitive detriment [1,2]
Assuming that the reduction of insoluble amyloid β-peptide (Aβ) aggregates may counteract the progressive degeneration occurring in AD, we have recently synthesized two series of N-alkyl carbazole derivatives (Figures 1 and 2) [28] here investigated in silico and in vitro for their ability to promote an increase of soluble Aβ peptides
It has been demonstrated that the intermolecular side-chain contacts responsible for fibril formations are formed between the odd-numbered residues of β strand 1 of the nth molecule and the even-numbered residues of β strand 2 of the (n−1)th molecule [30] (PDB code 2BEG)
Summary
Alzheimer’s disease (AD) is an age-related disorder that affects brain cells, leads to the inability to conduct a normal life and because of the chronic and progressive cognitive detriment [1,2]. The neuropathological hallmarks of AD include abundant deposits of amyloid β (Aβ) peptides organized in senile plaques, accumulation of hyperphosphorylated tau protein in neurofibrillary tangles, and extensive neuronal degeneration and loss. Aβ is a small self-aggregating molecule deriving from proteolytic processing of the amyloid precursor protein (APP). Inhibitors [26]; carbazole thiazoles are efficient, in vitro, in inhibiting β-amyloid formation [13], some dibenzofuran/carbazole derivatives show an improved anti-AD activity, combining the cholinesterase. Assuming that the reduction of insoluble Aβ aggregates may counteract the progressive degeneration occurring in AD, we have recently synthesized two series of N-alkyl carbazole derivatives (Figures 1 and 2) [28] here investigated in silico and in vitro for their ability to promote an increase of soluble Aβ peptides
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