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Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of β-amyloid (Aβ) in the form of senile plaques, and Aβ insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aβ-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 μM Aβ for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aβ. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsβ, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.
This article was published in the following journal.
Name: Chemico-biological interactions
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Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
A precursor to the AMYLOID BETA-PROTEIN (beta/A4). Alterations in the expression of the amyloid beta-protein precursor (ABPP) gene, located on chromosome 21, plays a role in the development of the neuropathology common to both ALZHEIMER DISEASE and DOWN SYNDROME. ABPP is associated with the extensive extracellular matrix secreted by neuronal cells. Upon cleavage, this precursor produces three proteins of varying amino acid lengths: 695, 751, and 770. The beta/A4 (695 amino acids) or beta-amyloid protein is the principal component of the extracellular amyloid in senile plaques found in ALZHEIMER DISEASE; DOWN SYNDROME and, to a limited extent, in normal aging.
A disintegrin and metalloproteinase domain-containing protein. It cleaves the membrane-bound precursor of TUMOR NECROSIS FACTOR-ALPHA between ALANINE 76 and VALINE 77 to its functional form, as well as several other CELL SURFACE PROTEINS to their soluble forms, including AMYLOID BETA-PROTEIN PRECURSOR and PRION PROTEIN.
A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.
Proteins that form the core of amyloid fibrils. For example, the core of amyloid A is formed from amyloid A protein, also known as serum amyloid A protein or SAA protein.
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