scholarly journals Clausena Harmandiana Root Extract Improved Amyloid-β Induced Cognitive Impairments in Rats By Reducing Aβ1-42 Protein Levels and Neuroinflammation

2022 ◽  
Author(s):  
Nutchareeporn Nillert ◽  
Chantana Boonyarat ◽  
Jariya Umka Welbat ◽  
Komsun Bunreungthong ◽  
Ploenthip Puthongking ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Recognition Memory ◽  
Normal Saline ◽  
Inflammatory Markers ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Root Extract ◽  
Sprague Dawley ◽  
Protein Levels

Abstract Background: Neuroinflammation caused by amyloid‐β (Aβ) is associated with Alzheimer’s disease (AD) pathogenesis. In AD, Aβ accumulation can activate the surrounding microglia which followed by the synthesis and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα), results in cognitive impairments. Clausena harmandiana (CH) is an herb in the Rutaceae family and has been used in folk medicine for the treatment of illness such as stomachache and headache, and as a health tonic. It is interesting that CH root extract (CHRE) exhibits various anti-inflammatory and other pharmacological activities, but there has not been any study in Alzheimer's disease-like animal models.Objectives: This study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive impairments, increased Aβ1-42 protein levels and neuroinflammation. Methods: Forty-eight adult male Sprague-Dawley rats (250-300 g) were randomly divided into 6 groups (n=8). The rats were given 0.5% sodium carboxymethylcellulose, Celebrex® (10 mg/kg BW) or CHRE (125, 250, and 500 mg/kg BW) and not given any treatment by oral gavage for 35 days. On day 21, all treated rats were injected with aggregated Aβ1-42 at a concentration of 1 µg/µl into both lateral ventricles (1 µl/side), while untreated rats were injected with sterilized normal saline. Ten days later, their recognition memory was assessed using the novel object recognition test. At the end of the experiment, all rats were euthanized by an overdose of thiopental sodium (120 mg/kg BW) and transcardial perfusion with 0.9% normal saline solution, to observe Aβ1-42 protein levels and the expression of inflammatory markers (CD11b-positive microglia, IL-1β, and TNFα) in the cerebral cortex and hippocampus.Results: The results indicated that pretreatment with CHRE at all doses improved impairment of short- and long-term recognition memory. In addition, CHRE significantly decreased Aβ1-42 protein levels and the expression of inflammatory markers in both brain regions as well as pretreatment with Celebrex®.Conclusions: This suggests that CHRE has a potential therapeutic effect against Aβ1-42-induced cognitive impairments by reducing Aβ1-42 protein levels and neuroinflammation.

scholarly journals Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Natalia Bezuch ◽  
Steven Bradburn ◽  
Andrew C. Robinson ◽  
Neil Pendleton ◽  
Antony Payton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Fluid Intelligence ◽  
Cpg Island ◽  
Amyloid Β ◽  
Superior Frontal Gyrus ◽  
Protein Levels ◽  
Apoe Protein ◽  
Apoe Locus

Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

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 Liver Growth Factor “LGF” as a Therapeutic Agent for Alzheimer’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9201
Author(s):  
Rafael Gonzalo-Gobernado ◽  
Juan Perucho ◽  
Manuela Vallejo-Muñoz ◽  
Maria José Casarejos ◽  
Diana Reimers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Amyloid Β ◽  
Dorsal Cortex ◽  
Liver Growth ◽  
Protein Levels ◽  
Protein Ubiquitination ◽  
Aging Populations ◽  
Degenerative Disorder

Alzheimer’s disease (AD) is a progressive degenerative disorder and the most common cause of dementia in aging populations. Although the pathological hallmarks of AD are well defined, currently no effective therapy exists. Liver growth factor (LGF) is a hepatic albumin–bilirubin complex with activity as a tissue regenerating factor in several neurodegenerative disorders such as Parkinson’s disease and Friedreich’s ataxia. Our aim here was to analyze the potential therapeutic effect of LGF on the APPswe mouse model of AD. Twenty-month-old mice received intraperitoneal (i.p.) injections of 1.6 µg LGF or saline, twice a week during three weeks. Mice were sacrificed one week later, and the hippocampus and dorsal cortex were prepared for immunohistochemical and biochemical studies. LGF treatment reduced amyloid-β (Aβ) content, phospho-Tau/Tau ratio and the number of Aβ plaques with diameter larger than 25 µm. LGF administration also modulated protein ubiquitination and HSP70 protein levels, reduced glial reactivity and inflammation, and the expression of the pro-apoptotic protein Bax. Because the administration of this factor also restored cognitive damage in APPswe mice, we propose LGF as a novel therapeutic tool that may be useful for the treatment of AD.

The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain

2007 ◽  
Vol 35 (3) ◽  
pp. 574-576 ◽  
Author(s):  
J.H. Stockley ◽  
C. O'Neill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Protein Levels ◽  
Rate Limiting Step ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
And Function

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing changes in β-secretase enzyme kinetics in AD brain caused by an increased Vmax. This article gives a brief review of studies which have examined BACE1 protein levels and β-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

scholarly journals Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

2021 ◽  
Vol 15 ◽  
Author(s):  
Frances M. Potjewyd ◽  
Alison D. Axtman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
E3 Ligase ◽  
Amyloid Β ◽  
3D Cell Culture ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Protein Levels ◽  
Chemical Tools

The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.

scholarly journals A Maitake (Grifola frondosa) polysaccharide ameliorates Alzheimer's disease-like pathology and cognitive impairments by enhancing microglial amyloid-β clearance

RSC Advances ◽  
2019 ◽  
Vol 9 (64) ◽  
pp. 37127-37135
Author(s):  
Yao Bai ◽  
Lingling Chen ◽  
Yao Chen ◽  
Xinmeng Chen ◽  
Yilong Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Grifola Frondosa

PGM ameliorates AD-like pathology and cognitive impairments by enhancing microglial amyloid-β clearance.

scholarly journals PGRN Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

2020 ◽  
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Xi-Peng Cao ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tgf Β1

Abstract Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

BACE1 and Other Alzheimer’s-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer’s Disease Patients from Cognitively-Impaired Neurosyphilis Patients

2020 ◽  
Vol 77 (1) ◽  
pp. 313-322 ◽  
Author(s):  
Min Zhang ◽  
Xiaomei Zhong ◽  
Haishan Shi ◽  
Eugeen Vanmechelen ◽  
Ann De Vos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Function ◽  
Amyloid Β ◽  
Cognitively Impaired ◽  
Protein Levels ◽  
Scale Scores ◽  
Early Biomarker ◽  
The Relationship

Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1–40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

scholarly journals Sex-Specific Effects of Chronic Creatine Supplementation on Hippocampal-Mediated Spatial Cognition in the 3xTg Mouse Model of Alzheimer’s Disease

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3589
Author(s):  
Wanda M. Snow ◽  
Chris Cadonic ◽  
Claudia Cortes-Perez ◽  
Aida Adlimoghaddam ◽  
Subir K. Roy Chowdhury ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Spatial Cognition ◽  
Creatine Supplementation ◽  
Amyloid Β ◽  
Western Blots ◽  
Protein Levels ◽  
Spatial Search ◽  
Model Of Alzheimer’S Disease

The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid β (Aβ) species, whereas Aβ trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.

scholarly journals Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicholas C. Cullen ◽  
A nders Mälarstig ◽  
Erik Stomrud ◽  
Oskar Hansson ◽  
Niklas Mattsson-Carlgren
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Chronological Age ◽  
Subjective Cognitive Decline ◽  
Protein Levels ◽  
Age Related ◽  
Inflammatory Proteins ◽  
Contrast Group ◽  
Inflammatory Changes

AbstractIt is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.

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