scholarly journals Therapeutic Potential of TNF-α Inhibition for Alzheimer’s Disease Prevention

2020 ◽  
Vol 78 (2) ◽  
pp. 619-626
Author(s):  
Noel Torres-Acosta ◽  
James H. O’Keefe ◽  
Evan L. O’Keefe ◽  
Richard Isaacson ◽  
Gary Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Cognitive Performance ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Blocking Agents ◽  
Populations At Risk ◽  
Tnf Α ◽  
Factor Α

Background: Alzheimer’s disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-α (TNF-α) have potential to improve cognitive performance. Objective: In this review, we summarize the evidence regarding the potential for TNF-α inhibition to prevent AD and improve cognitive function in people at risk for dementia. Methods: We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-α inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α, TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin. Results: Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-α, showed enhanced cognitive performance and decreased brain levels of amyloid-β plaque and tau tangles. Conclusion: TNF-α targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD.

Connection of lipid peroxide oxidation with the sphingomyelin pathway in the development of Alzheimer's disease

2004 ◽  
Vol 32 (1) ◽  
pp. 144-146 ◽  
Author(s):  
A.V. Alessenko ◽  
A.E. Bugrova ◽  
L.B. Dudnik
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Amyloid Β ◽  
Lipid Peroxide ◽  
Intracerebral Injection ◽  
Amyloid Β Peptide ◽  
Peroxide Oxidation ◽  
Tnf Α ◽  
Factor Α

Alzheimer's disease (AD) is characterized by progressive decline in cognition, memory and intellect. It has been hypothesized that amyloid-β peptide (A-β) may have a prominent role in neurodegeneration. Oxidative mechanisms have been implicated in this pathway. There is substantial evidence that inflammatory mechanisms, induced by tumour necrosis factor α (TNF-α), are also involved in AD. TNF-α activates receptors linked to multiple effector systems, including a sphingomyelin pathway and peroxide oxidation. We have determined the changes of neutral sphingomyelinase activity, sphingomyelin and ceramide contents, and the level of lipid peroxide products (conjugated dienes), in the cerebral cortex, hippocampus and cerebellum of rats within 3 h and 7 days of intracerebral injection of A-β and TNF-α. A single injection of A-β and TNF-α has been shown to increase the level of peroxide products in the hippocampus and cerebral cortex within 3 h and 7 days. Sphingomyelinase activity and ceramide levels have been found to increase 7 days after A-β administration. We found that activation of the sphingomyelin pathway lies downstream from the oxidative stress.

scholarly journals Tumor necrosis factor α Inhibition for Alzheimer’s Disease

2017 ◽  
Vol 9 ◽  
pp. 117957351770927 ◽  
Author(s):  
Rudy Chang ◽  
Kei-Lwun Yee ◽  
Rachita K Sumbria
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Short Review ◽  
Tnf Α ◽  
Factor Α ◽  
Ad Therapy ◽  
Necrosis Factor

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

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

Brain ◽  
2018 ◽  
Vol 142 (1) ◽  
pp. 176-192 ◽  
Author(s):  
Bing-Lin Zhu ◽  
Yan Long ◽  
Wei Luo ◽  
Zhen Yan ◽  
Yu-Jie Lai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Translation Initiation Factor ◽  
Precursor Protein ◽  
Initiation Factor ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Model Of Alzheimer’S Disease

AbstractMMP13 (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 screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

scholarly journals Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

2020 ◽  
Vol 14 ◽  
Author(s):  
Antonio Munafò ◽  
Chiara Burgaletto ◽  
Giulia Di Benedetto ◽  
Marco Di Mauro ◽  
Rosaria Di Mauro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Drug Repositioning ◽  
Amyloid Β ◽  
Deep Understanding ◽  
Current Status ◽  
Age Related ◽  
Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

EXPOSURE TO AIR POLLUTION AND COGNITIVE PERFORMANCE OF HEALTHY INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE

2017 ◽  
Vol 13 (7) ◽  
pp. P564-P565
Author(s):  
Gonzalo Sánchez-Benavides ◽  
Mireia Gascón ◽  
Nina Gramunt ◽  
Xavier Gotsens ◽  
Karine Fauria ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Air Pollution ◽  
Cognitive Performance ◽  
Healthy Individuals

scholarly journals Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

2019 ◽  
Vol 15 (6) ◽  
pp. 764-775 ◽  
Author(s):  
Andrea Vergallo ◽  
Lucile Mégret ◽  
Simone Lista ◽  
Enrica Cavedo ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Amyloid Β ◽  
Cognitively Normal ◽  
Cerebral Amyloidosis ◽  
Normal Individuals

scholarly journals P3-264: PERIPHERAL AND CENTRAL INFLAMMATION DIFFER BY RACE AND ASSOCIATE WITH COGNITIVE PERFORMANCE IN A POPULATION AT RISK FOR ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P1037-P1038
Author(s):  
Lori N. Eidson ◽  
Kaitlin Sandor ◽  
Vicki Hertzberg ◽  
Amarallys F. Cintron ◽  
Jianjun Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Cognitive Performance ◽  
Population At Risk

The therapeutic potential of natural compounds against Alzheimer's disease: A preclinical pharmacological study in both sexes

2016 ◽  
Vol 33 (S1) ◽  
pp. S544-S544
Author(s):  
N. Kokras ◽  
M. Dimitriadou ◽  
I. Sotiropoulos ◽  
A.L. Skaltsounis ◽  
A. Tsarbopoulos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Locomotor Activity ◽  
Cognitive Performance ◽  
Therapeutic Potential ◽  
Pharmacological Study ◽  
Natural Compounds ◽  
Crocus Sativus ◽  
Male And Female ◽  
Pharmacological Studies

Alzheimer's disease (AD), a neurodegenerative neuropsychiatric disorder, is often comorbid with depression and anxiety. Neuropsychiatric disorders are also characterized by sex differences. However, most preclinical pharmacological studies are conducted using only males. Herein, we used male and female twelve-month-old mice (3xTg) expressing mutated forms of human proteins Tau, APP and Presenilin1. These mice are considered a valid animal model of AD. We investigated the effects of the natural compound trans-crocin-4 (TC-4), which is derived from Crocus sativus and the olive compound oleuropein on the cognitive, depressive and anxious profile of 3xTg mice. We found that male and female 3xTg mice exhibited reduced locomotor activity and oleuropeine treatment (100 mg/kg i.p., for 21 days) did not reverse this phenotype. In addition, anxiety- and depressive-like behaviors were not affected by genotype, sex or oleuropeine treatment. Interestingly, oleuropeine exhibited a tendency to enhance cognitive performance in male 3xTg mice. Treatment with TC-4 (50 and 150 mg/kg, i.p., acutely or chronically for 10 days) affected locomotor activity in a sex-differentiated manner. Interestingly, acute TC-4 clearly enhanced cognitive performance in all groups although it reduced center entries in the open field. Additionally, chronic TC-4 treatment enhanced novel object discrimination mainly in male 3xTg mice. Our findings highlight the potential of those natural compounds, which warrant further investigation but also emphasize the benefits of including both males and females in preclinical pharmacological studies.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer’s Disease

2019 ◽  
Vol 71 (3) ◽  
pp. 775-783 ◽  
Author(s):  
Pratishtha Chatterjee ◽  
Mitra Elmi ◽  
Kathryn Goozee ◽  
Tejal Shah ◽  
Hamid R. Sohrabi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Amyloid Β ◽  
Ultrasensitive Detection ◽  
Cognitively Normal ◽  
Elderly Individuals
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