A BODIPY biosensor to detect and drive self-assembly of diphenylalanine

2019 ◽  
Vol 55 (59) ◽  
pp. 8564-8566
Author(s):  
Li Quan ◽  
Jianhua Gu ◽  
Wenhai Lin ◽  
Yanchun Wei ◽  
Yuebin Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Self Assembly ◽  
Early Onset ◽  
Recognition Motif ◽  
Amyloid Aβ ◽  
Β Amyloid

Diphenylalanine (FF), as the smallest unit and core recognition motif of β-amyloid (Aβ), could self-assemble into nanofibers, which induces an early onset of Alzheimer's disease (AD).

scholarly journals Target-driven supramolecular self-assembly for selective amyloid-β photooxygenation against Alzheimer's disease

2020 ◽  
Vol 11 (40) ◽  
pp. 11003-11008
Author(s):  
Zhenqi Liu ◽  
Mengmeng Ma ◽  
Dongqin Yu ◽  
Jinsong Ren ◽  
Xiaogang Qu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photodynamic Therapy ◽  
Self Assembly ◽  
Amyloid Β ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid

Photo-oxygenation of β-amyloid (Aβ) has been considered an efficient way to inhibit Aβ aggregation in Alzheimer's disease (AD). We present the first example of Aβ-responsive photodynamic therapy to treatment of AD by using PKNPs self-assemblies.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

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

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
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.

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

2005 ◽  
Vol 171 (1) ◽  
pp. 87-98 ◽  
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.

Distance-based β-amyloid protein detection on PADs for scanning and subsequent follow up of Alzheimer’s disease in human urine sample

The Analyst ◽  
2022 ◽  
Author(s):  
Kawin Khachornsakkul ◽  
Anongnat Tiangtrong ◽  
Araya Suwannasom ◽  
Wuttichai Sangkharoek ◽  
Opor Jamjumrus ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Urine ◽  
Protein Detection ◽  
Protein Quantification ◽  
Amyloid Protein ◽  
Human Urine Sample ◽  
Amyloid Aβ ◽  
Β Amyloid

We report on the first development of a simple distance-based β-amyloid (Aβ) protein quantification using paper-based devices (dPADs) to screen for Alzheimer’s disease (AD) and to subsequently follow up on...

scholarly journals Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

2020 ◽  
Vol 6 (33) ◽  
pp. eabb9036
Author(s):  
Bradlee L. Heckmann ◽  
Brett J. W. Teubner ◽  
Emilio Boada-Romero ◽  
Bart Tummers ◽  
Clifford Guy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Disease ◽  
Memory Impairment ◽  
Memory Loss ◽  
Tau Hyperphosphorylation ◽  
Primary Microglia ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

scholarly journals Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer’s Disease in a Preclinical Model: A Therapeutic Opportunity

Biology ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 377
Author(s):  
Dina Medina-Vera ◽  
Cristina Rosell-Valle ◽  
Antonio J. López-Gambero ◽  
Juan A. Navarro ◽  
Emma N. Zambrana-Infantes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Receptor Expression ◽  
Preclinical Model ◽  
Diacylglycerol Lipase ◽  
Therapeutic Opportunity ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
5Xfad Mice ◽  
Old Mice

Alzheimer’s disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer’s disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and β-amyloid (Aβ) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aβ’s accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aβ deposition.

scholarly journals Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2182 ◽  
Author(s):  
Luca Piemontese ◽  
Gabriele Vitucci ◽  
Marco Catto ◽  
Antonio Laghezza ◽  
Filippo Perna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Characteristics ◽  
Biological Properties ◽  
Cognitive Capacity ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Ad Therapy ◽  
Target Activity

A few symptomatic drugs are currently available for Alzheimer’s Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of β-amyloid (Aβ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 ± 0.2 μmol/µmol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 ± 0.67 μM) and Aβ1–40 aggregation (IC50 = 74 ± 1 μM). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 ± 0.59 μM) with a good selectivity toward AChE (IC50 = 86.0 ± 15.0 μM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).

scholarly journals An antibody against HK blocks Alzheimer’s disease peptide β-amyloid−induced bradykinin release in human plasma

2019 ◽  
Vol 116 (46) ◽  
pp. 22921-22923 ◽  
Author(s):  
Zu-Lin Chen ◽  
Pradeep Singh ◽  
Jyen Wong ◽  
Katharina Horn ◽  
Sidney Strickland ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Weight ◽  
Septic Shock ◽  
Traumatic Injury ◽  
Plasma Kallikrein ◽  
High Molecular Weight Kininogen ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Proinflammatory Factor

Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer’s disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent downstream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide β-amyloid (Aβ)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.

Sign in / Sign up

Export Citation Format

Share Document