scholarly journals Porphyromonas gingivalisin Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

2019 ◽  
Vol 5 (1) ◽  
pp. eaau3333 ◽  
Author(s):  
Stephen S. Dominy ◽  
Casey Lynch ◽  
Florian Ermini ◽  
Malgorzata Benedyk ◽  
Agata Marczyk ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Bacterial Load ◽  
Brain Infection ◽  
Disease Causation ◽  
The Brain

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. OralP. gingivalisinfection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an establishedP. gingivalisbrain infection, blocked Aβ1–42production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treatingP. gingivalisbrain colonization and neurodegeneration in Alzheimer’s disease.

scholarly journals Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xun Gao ◽  
Yuanyuan Xu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Natural Compounds ◽  
Therapeutic Effects

Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive cognitive impairment and memory loss. So far, the pathogenesis of AD has not been fully understood. Research have shown that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) participate in the occurrence and development of AD. Furthermore, various studies, both in vivo and in vitro, have shown that targeting ER stress and ER stress-mediated apoptosis contribute to the recovery of AD. Thus, targeting ER stress and ER stress-mediated apoptosis may be effective for treating AD. In this review, the molecular mechanism of ER stress and ER stress-mediated apoptosis, as well as the therapeutic effects of some natural compounds and small molecule inhibitors targeting ER stress and ER stress-mediated apoptosis in AD will be introduced.

scholarly journals Alternative Treatment for Alzheimer’s Disease: Porphyromonas gingivalis Inhibitors

2019 ◽  
pp. 23-25
Author(s):  
Pouriya Sadeghighazichaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Virulence Factor ◽  
Bacterial Load ◽  
Amyloid Plaque ◽  
Plaque Deposition ◽  
The Brain

Porphyromonas gingivalis (P. gingivalis), has been identified as a primary pathogen in causing chronic periodontitis, or gum inflammation. P. gingivalis was also isolated in brain samples of patients suffering from Alzheimer’s disease. A virulence factor of P. gingivalis called gingipains, releases proteases responsible for neurodegeneration and has been identified in the brain of patients suffering from Alzheimer’s. Studies show that mice infected with P. gingivalis demonstrate an increase in amyloid plaque deposition in brain samples. Further investigation identified gingipains as a neurotoxic agent, both in vivo and in vitro, which impacts the structure of tau protein, responsible for the normal functioning of neurons. Small-molecule inhibitors targeting gingipains are utilized to prevent the neurotoxic effects of gingipains and facilitate neuronal regeneration. Inhibition of this virulence factor reduced the overall bacterial load, blocked amyloid-beta production, prevented neuroinflammation, and allowed for neuronal recovery. These findings provide a new outlook for the onset of Alzheimer’s disease and elucidate a much-needed potential treatment for the condition.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

scholarly journals Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

2021 ◽  
Vol 22 (23) ◽  
pp. 13136
Author(s):  
Han Seok Koh ◽  
SangJoon Lee ◽  
Hyo Jin Lee ◽  
Jae-Woong Min ◽  
Takeshi Iwatsubo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Treatment Strategies ◽  
Tau Pathology ◽  
Memory Decline ◽  
Tnf Α ◽  
The Brain

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

scholarly journals Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Malcolm Roberts ◽  
Ioanna Sevastou ◽  
Yoichi Imaizumi ◽  
Kavita Mistry ◽  
Sonia Talma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Model ◽  
Sequence Motif ◽  
Antibody Treatment ◽  
Microtubule Binding ◽  
High Affinity ◽  
The Brain

AbstractTau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

scholarly journals Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer’s Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Valeriy G. Ostapchenko ◽  
Jonatan Snir ◽  
Mojmir Suchy ◽  
Jue Fan ◽  
M. Rebecca Cobb ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Caspase 3 ◽  
Single Cells ◽  
Glucose Deprivation ◽  
Apoptotic Cells ◽  
The Brain

Apoptosis is a feature of stroke and Alzheimer’s disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [68Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and 68Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [68Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA labeled apoptotic neurons following exposure to camptothecin, oxygen-glucose deprivation, and β-amyloid oligomers. In vivo, PET showed accumulation of [68Ga]Ga-TC3-OGDOTA in the brain of mouse models of stroke or AD. Optical clearing revealed colocalization of [68Ga]Ga-TC3-OGDOTA and cleaved caspase-3 in brain cells. In stroke, [68Ga]Ga-TC3-OGDOTA accumulated in neurons in the penumbra area, whereas in AD mice [68Ga]Ga-TC3-OGDOTA was found in single cells in the forebrain and diffusely around amyloid plaques. In summary, this bifunctional tracer is selectively associated with apoptotic cells in vitro and in vivo in brain disease models and represents a novel tool for apoptosis detection that can be used in neurodegenerative diseases.

scholarly journals CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTL in vivo over-expression has a mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

Discovery of a novel small molecule PT109 with multi-targeted effects against Alzheimer's disease in vitro and in vivo

2020 ◽  
Vol 883 ◽  
pp. 173361
Author(s):  
Qiuhe Chen ◽  
Yalin Tu ◽  
Shinghung Mak ◽  
Jingkao Chen ◽  
Junfeng Lu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule

scholarly journals Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

2020 ◽  
Vol 13 ◽  
Author(s):  
Madeleine R. Brown ◽  
Sheena E. Radford ◽  
Eric W. Hewitt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Aβ Fibrils ◽  
The Brain

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

Sign in / Sign up

Export Citation Format

Share Document