scholarly journals Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2581
Author(s):  
Jade de Oliveira ◽  
Ewa Kucharska ◽  
Michelle Lima Garcez ◽  
Matheus Scarpatto Rodrigues ◽  
João Quevedo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metabolic Diseases ◽  
Late Onset ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Inflammatory Cascade ◽  
Anti Inflammatory ◽  
Experimental Findings

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood–brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.

scholarly journals A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death

2014 ◽  
Vol 20 (12) ◽  
pp. 1452-1457 ◽  
Author(s):  
Monica K Wetzel-Smith ◽  
◽  
Julie Hunkapiller ◽  
Tushar R Bhangale ◽  
Karpagam Srinivasan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Late Onset ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rare Mutation

scholarly journals Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer’s disease pathologies

2021 ◽  
Vol 7 (16) ◽  
pp. eabe4499
Author(s):  
Guiqin Chen ◽  
Seong Su Kang ◽  
Zhihao Wang ◽  
Eun Hee Ahn ◽  
Yiyuan Xia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Axon Guidance ◽  
Neural Development ◽  
Caspase 3 ◽  
Late Onset ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cognitive Disorders

Netrin-1, a family member of laminin-related secreted proteins, mediates axon guidance and cell migration during neural development. T835M mutation in netrin receptor UNC5C predisposes to the late-onset Alzheimer’s disease (AD) and increases neuronal cell death. However, it remains unclear how this receptor is molecularly regulated in AD. Here, we show that δ-secretase selectively cleaves UNC5C and escalates its proapoptotic activity, facilitating neurodegeneration in AD. Netrin deficiency activates δ-secretase that specifically cuts UNC5C at N467 and N547 residues and enhances subsequent caspase-3 activation, additively augmenting neuronal cell death. Blockade of δ-secretase cleavage of UNC5C diminishes T835M mutant’s proapoptotic activity. Viral expression of δ-secretase–truncated UNC5C fragments into APP/PS1 mice strongly accelerates AD pathologies, impairing learning and memory. Conversely, deletion of UNC5C from netrin-1–depleted mice attenuates AD pathologies and rescues cognitive disorders. Hence, δ-secretase truncates UNC5C and elevates its neurotoxicity, contributing to AD pathogenesis.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

scholarly journals Annona atemoya leaf extract ameliorates cognitive impairment in amyloid-β injected Alzheimer’s disease-like mouse model

2019 ◽  
Vol 244 (18) ◽  
pp. 1665-1679 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Eunjin Sohn ◽  
Jiyeon Yoon ◽  
Bu-Yeo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell Death ◽  
Growth Factor Receptor ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Bioactive Compound ◽  
Aβ Aggregation ◽  
Epidermal Growth ◽  
G Protein Coupled

Annona atemoya is a hybrid of Annona squamosa and Annona cherimola that grow in several subtropical or tropical areas such as Florida in the US, Philippines, Cuba, Jamaica, Taiwan, and Jeju in South Korea. We report that the A. atemoya leaves (AAL) have inhibitory effects on the pathogenesis and regulatory mechanisms of Alzheimer’s disease (AD). Ethanol extract of AAL prevented amyloid-β (Aβ) aggregation and increased free radical scavenging activity. In addition, AAL extract exerted protective effects against neuronal cell death in HT22 hippocampal cells. Moreover, oral administration of AAL extract significantly improved memory loss in the passive avoidance task and Y-maze test, as well as downregulated the expression of neuronal markers neuronal nuclei and brain-derived neurotrophic factor in Aβ-injected AD mice. To verify the molecular mechanisms responsible for anti-AD actions of AAL, we conducted the antibody microarray analysis and found that epidermal growth factor receptor/G protein-coupled receptor kinase 2 signaling was activated in neuronal cells and AD-like mouse models. Additionally, quantitative analyses of the six standard compounds using high-performance liquid chromatography revealed that rutin is the most abundant compound of AAL. Furthermore, efficacy analyses of six standard compounds showed that rutin and isoquercitrin had significant inhibitory activity on Aβ aggregation. Taken together with biological activity and the content of compounds, rutin maybe a bioactive compound of AAL in the AD pathogenesis. Overall, our findings provide the first scientific support for the therapeutic effects of AAL in AD and AD-related disorders. Impact statement Our study was aimed to find a novel candidate drug for Alzheimer’s disease (AD) using natural products. We assessed the effects of Annona atemoya extracts on crucial events in the pathogenesis of AD. A. atemoya leaf (AAL) extract significantly inhibited amyloid-β aggregation, oxidative stress, neuronal cell death, and memory impairment through the epidermal growth factor receptor/G protein-coupled receptor kinase 2 pathway. Simultaneous analysis using HPLC determined six standard compounds of AAL extract, and rutin was identified as a bioactive compound. Of note, the anti-AD activity of AAL extract was more significant compared to other extracts from medicinal plants of which efficacy was previously reported. The potential of AAL extract as an anti-AD agent may provide insight into the new drug development for AD treatment.

Interactions between BIM Protein and Beta-Amyloid May Reveal a Crucial Missing Link between Alzheimer’s Disease and Neuronal Cell Death

2019 ◽  
Vol 10 (8) ◽  
pp. 3555-3564 ◽  
Author(s):  
Ravit Malishev ◽  
Sukhendu Nandi ◽  
Dariusz Śmiłowicz ◽  
Shamchal Bakavayev ◽  
Stanislav Engel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Beta Amyloid ◽  
Missing Link

scholarly journals Direct and Indirect Roles of Cyclin-dependent Kinase 5 as an Upstream Regulator in the c-Jun NH2-Terminal Kinase Cascade: Relevance to Neurotoxic Insults in Alzheimer's Disease

2009 ◽  
Vol 20 (21) ◽  
pp. 4611-4619 ◽  
Author(s):  
Kai-Hui Sun ◽  
Hyoung-gon Lee ◽  
Mark A. Smith ◽  
Kavita Shah
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Second Phase ◽  
Jnk Pathway ◽  
Upstream Regulator ◽  
Kinase Cascade

Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c-Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun.

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