Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

BACE1 is the rate-limiting enzyme involved in the production and deposition of β-amyloid (Aβ). Since neurotoxic Aβ plays a critical role in Alzheimer’s disease (AD) pathogenesis, BACE1 has emerged as a key target for preventing AD. In the present study, the potential of sulforaphane, an isothiocyanate found in cruciferous vegetables, as a BACE1 inhibitor has been investigated. Sulforaphane exhibited six times more potent activity against BACE1 compared to well-known positive controls including resveratrol and quercetin. Sulforaphane presented selective and non-competitive BACE1 inhibitory activity with low off-target inhibition of BACE2 and other aspartic and serine proteases. In addition, sulforaphane presented negative binding energy, suggesting that the compound had a high affinity for BACE1. It interacted with locations other than the active binding sites of BACE1 through van der Waals forces. Overall, sulforaphane appeared to be a promising candidate with potent and selective BACE1 inhibitory properties that play an important role in AD prevention.

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

10.26434/chemrxiv.12445505 ◽

2020 ◽

Author(s):

Liang Sun ◽

Anuj K. Sharma ◽

Byung-Hee Han ◽

Liviu M. Mirica

Keyword(s):

Reactive Oxygen Species ◽

Metal Ions ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Amyloid Plaques ◽

Transition Metal Ions ◽

Oxygen Species ◽

High Affinity ◽

Amyloid Aβ ◽

Β Amyloid

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu2+ with very high affinity (pCu7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (Ki = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ42 aggregation and disaggregation of Aβ42 fibrils was also investigated, to reveal that AMF can control the formation of neurotoxic soluble Aβ42 oligomers, both in absence and presence of metal ions, and as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu2+ and significantly diminish the Cu2+-ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity, can also bind Cu2+ and mediate its deleterious redox properties, and thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.

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MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Current Neurovascular Research ◽

10.2174/1567202617666200128141938 ◽

2020 ◽

Vol 17 (1) ◽

pp. 93-101 ◽

Cited By ~ 3

Author(s):

Dan Wang ◽

Zhifu Fei ◽

Song Luo ◽

Hai Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Western Blot ◽

Mrna Expression ◽

Cognitive Deficits ◽

Protein Levels ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

International Journal of Molecular Sciences ◽

10.3390/ijms22031031 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1031

Author(s):

Naoko Niimi ◽

Hideji Yako ◽

Shizuka Takaku ◽

Sookja K. Chung ◽

Kazunori Sango

Keyword(s):

Schwann Cells ◽

Aldose Reductase ◽

Critical Role ◽

Polyol Pathway ◽

Glucose Flux ◽

Rate Limiting ◽

Deficient Mice ◽

Excess Glucose ◽

Shed Light ◽

Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

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Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Nutrients ◽

10.3390/nu13030985 ◽

2021 ◽

Vol 13 (3) ◽

pp. 985

Author(s):

Luisa Müller ◽

Nicole Power Guerra ◽

Jan Stenzel ◽

Claire Rühlmann ◽

Tobias Lindner ◽

...

Keyword(s):

Caloric Restriction ◽

Neuroprotective Effect ◽

Resonance Spectroscopy ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Positron Emission ◽

Pet Ct ◽

Amyloid Aβ ◽

Β Amyloid

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

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Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

Science Advances ◽

10.1126/sciadv.abe4601 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabe4601

Author(s):

Sandro Da Mesquita ◽

Jasmin Herz ◽

Morgan Wall ◽

Taitea Dykstra ◽

Kalil Alves de Lima ◽

...

Keyword(s):

T Cells ◽

Cognitive Decline ◽

Brain Aging ◽

Therapeutic Potential ◽

T Cell Response ◽

Age Related ◽

Lymphatic Vasculature ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

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A short synthesis of the β-amyloid (Aβ) aggregation inhibitor 3-p-Toluoyl-2-[4′-(3-diethylaminopropoxy)-phenyl]-benzofuran

Tetrahedron Letters ◽

10.1016/s0040-4039(99)02030-4 ◽

1999 ◽

Vol 40 (52) ◽

pp. 9383-9384 ◽

Cited By ~ 37

Author(s):

Lance J. Twyman ◽

David Allsop

Keyword(s):

Aβ Aggregation ◽

Short Synthesis ◽

Amyloid Aβ ◽

Β Amyloid ◽

Aggregation Inhibitor

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Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316551 ◽

2017 ◽

Vol 89 (5) ◽

pp. 456-460 ◽

Cited By ~ 26

Author(s):

Scott Ayton ◽

Ibrahima Diouf ◽

Ashley Ian Bush

Keyword(s):

Disease Process ◽

Threshold Value ◽

Simulation Modelling ◽

Longitudinal Changes ◽

Accelerated Depreciation ◽

History Of ◽

Amyloid Aβ ◽

Β Amyloid ◽

Using Data ◽

Alzheimer’S Pathology

ObjectiveTo investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau.MethodsMixed-effects models of CSF Aβ1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ1-42 for up to 5 years.ResultsIn subjects with biomarker-confirmed Alzheimer’s pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer’s subjects from 18.8 to 10.8 years.ConclusionsIron might facilitate Aβ deposition in Alzheimer’s and accelerate the disease process.

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Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

The Journal of Cell Biology ◽

10.1083/jcb.200505082 ◽

2005 ◽

Vol 171 (1) ◽

pp. 87-98 ◽

Cited By ~ 590

Author(s):

W. Haung Yu ◽

Ana Maria Cuervo ◽

Asok Kumar ◽

Corrinne M. Peterhoff ◽

Stephen D. Schmidt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Survival ◽

Mammalian Target Of Rapamycin ◽

Amyloid Peptide ◽

Survival Pathways ◽

Secretase Activity ◽

Amyloid Aβ ◽

Β Amyloid ◽

Β Amyloid Peptide

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

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