Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway.

08:00 EDT 10th June 2019 | BioPortfolio

Summary of "Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway."

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.


Journal Details

This article was published in the following journal.

Name: Chemico-biological interactions
ISSN: 1872-7786


DeepDyve research library

PubMed Articles [15814 Associated PubMed Articles listed on BioPortfolio]

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease.

Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ...

The crystal structure of amyloid precursor-like protein 2 E2 domain completes the amyloid precursor protein family.

The amyloid precursor-like protein 2 (APLP2) molecule is a type I transmembrane protein that is crucial for survival, cell-cell adhesion, neuronal development, myelination, cancer metastasis, modulati...

Therapeutic potential of cyanobacterial pigment protein phycoerythrin: in silico and in vitro study of BACE1 interaction and in vivo Aβ reduction.

Cyanobacteria are an immense source of innovative classes of pharmacologically active compounds exhibiting various biological activities ranging from antioxidants, antibiotics, anticancer, anti-inflam...

The cyanobacterial neurotoxin β-N-methylamino-l-alanine prevents addition of heparan sulfate to glypican-1 and increases processing of amyloid precursor protein in dividing neuronal cells.

The neurotoxin β-N-methylamino-l-alanine replaces l-serine in proteins and produces Alzheimer-like pathology. In proteoglycans, e.g. glypican-1, this should preclude substitution with heparan sulfate...

MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation.

MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer's disease. In this study, we used high-throughput small molecule ...

Clinical Trials [5115 Associated Clinical Trials listed on BioPortfolio]

Hypertension, Intracranial Pulsatility and Brain Amyloid-beta Accumulation in Older Adults (HIPAC Trial)

The aim of this study is to determine if lowering blood pressure using FDA approved medication (antihypertensive drugs) alters brain pulsatility and reduces brain amyloid beta protein accu...

Application of Amyloid PET in Cerebral Amyloid Angiopathy

In this project, we will try to enhance the diagnostic potentials of amyloid PET in CAA by combination of dynamic amyloid PET with MRI SWI and MR perfusion images. We will also try to inve...

Vascular Effects of Hesperidin in Metabolic Syndrome

It has been suggested that cardiovascular risk factors either independently or in cluster (metabolic syndrome) increase the risk of both type 2 diabetes (DM2) and cardiovascular diseases (...

Safety Study of Passive Immunization for Patients With Mild to Moderate Alzheimer's Disease

This research study will assess whether AAB-001 is safe, well tolerated and effective for use in patients with Alzheimer's Disease. AAB-001 is a new drug that is not available outside thi...

Effect of EGb 761® on Patients With Mild to Moderate Alzheimer's Disease

The aim of this study is to measure the effect of EGb 761® versus placebo on the ratio of the isoform of the protein precursor of beta amyloid platelets, in patients with mild to moderate...

Medical and Biotech [MESH] Definitions

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.

Quick Search


DeepDyve research library

Relevant Topics

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...

Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...

Searches Linking to this Article