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

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.

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

Brain ◽

10.1093/brain/awy305 ◽

2018 ◽

Vol 142 (1) ◽

pp. 176-192 ◽

Cited By ~ 13

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21239201 ◽

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.

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

Biochemical Society Transactions ◽

10.1042/bst0350574 ◽

2007 ◽

Vol 35 (3) ◽

pp. 574-576 ◽

Cited By ~ 32

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.

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New pharmacological strategies for the treatment of alzheimer’s disease

10.5327/1516-3180.097 ◽

2021 ◽

Author(s):

Letícia Freitas de Castro Silva ◽

Elisa Pinheiro Weber ◽

Gleice Silva Toledo ◽

Josiane Fonseca Almeida

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Tau Protein ◽

Amyloid Β ◽

The Elderly ◽

New Drugs ◽

Pathophysiological Mechanisms ◽

Apoe Protein ◽

New Biomarkers

Introduction: Alzheimer’s disease (AD) is seen as the most important dementia, prevalent in the elderly over 60 years old. There is still no cure, and the pharmacological strategies are to delay the symptoms and development of the pathology. The pathophysiological mechanisms are: hyperphosphorylation of the tau protein and aggregation of amyloid-β. Update studies of the tested therapies target the main pathological mechanisms: accumulation of β amyloid (inhibitors and modulators of β-secretase and γ-secretase and active and passive anti-Aβ immunotherapies), tau protein (inhibition of abnormal hyperphosphorylation with GSK-3 inhibitors, passive and active immunotherapies and the use of intrathecal antisense oligonucleotides (ASOs) and correction of the ApoE protein (increase lipidation, correct structure, clearance of non-lipid ApoE and reduction of ApoE expression). Objectives and methodology: To develop a bibliographic review in order to address new drugs in the treatment of Alzheimer’s. Qualitative and descriptive study carried out by literary review with research on PubMed. Results: Several drugs have been tested in clinical trials, however, due to lack of effectiveness, none have been approved. Therefore, it’s important to understand the limitations of the tests developed as flaws in the methodology, insufficient understanding of the mechanisms involved and inclusion of patients in different stages of AD, so that future investigations can overcome these gaps. Conclusion: It’s important to investigate new pathophysiological mechanisms, as well as the factors that trigger AD. Diagnosis is essential, with further studies to identify new biomarkers of the disease that will also have an impact on the conduct of clinical trials.

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.768655 ◽

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.

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Amyloid-β Alters the DNA Methylation Status of Cell-fate Genes in an Alzheimer's Disease Model

Journal of Alzheimer s Disease ◽

10.3233/jad-131061 ◽

2013 ◽

Vol 38 (4) ◽

pp. 831-844 ◽

Cited By ~ 11

Author(s):

Noor Taher ◽

Courtney McKenzie ◽

Rebecca Garrett ◽

Matthew Baker ◽

Nena Fox ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Cell Fate ◽

Methylation Status ◽

Disease Model ◽

Amyloid Β

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

Journal of Alzheimer s Disease ◽

10.3233/jad-200362 ◽

2020 ◽

Vol 77 (1) ◽

pp. 313-322 ◽

Cited By ~ 1

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.

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

Nutrients ◽

10.3390/nu12113589 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-021-81705-7 ◽

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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