Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer’s Disease-Like Mouse Model

2019 ◽  
Vol 16 (9) ◽  
pp. 861-870 ◽  
Author(s):  
Roy Lardenoije ◽  
Daniël L.A. van den Hove ◽  
Sophie E. Jung ◽  
Monique Havermans ◽  
Peter Blackburn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Amyloid Β ◽  
Active Immunization ◽  
Active Immunotherapy ◽  
Dna Hydroxymethylation ◽  
Synaptic Markers ◽  
The Impact

Background: While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far. Objective: The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice. Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition. Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A. Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.

scholarly journals Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna A. Lauer ◽  
Daniel Janitschke ◽  
Malena dos Santos Guilherme ◽  
Vu Thu Thuy Nguyen ◽  
Cornel M. Bachmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Lipid Homeostasis ◽  
Medical Surveillance ◽  
Shotgun Lipidomics ◽  
App Processing ◽  
Cognitive Improvement ◽  
The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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 Perphenazine-macrocycle conjugates divert Aβ42 towards non-toxic aggregates by monomer sequestration

2020 ◽  
Author(s):  
Sarah R Ball ◽  
Julius S P Adamson ◽  
Michael A Sullivan ◽  
Manuela R Zimmermann ◽  
Victor Lo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmr Spectroscopy ◽  
Kinetic Analysis ◽  
Amyloid Β ◽  
Dimensional Structure ◽  
Amyloid Β Peptide ◽  
Monomeric Form ◽  
Starting Point ◽  
The Impact

AbstractThe amyloid-β peptide, the main protein component of amyloid plaques in Alzheimer’s disease, plays a key role in the neurotoxicity associated with the condition through the formation of small toxic oligomer species which mediate the disruption of calcium and glutamate homeostasis. The lack of therapeutic benefit associated with removal of mature amyloid-β fibrils has focused attention on the toxic oligomeric species formed during the process of fibril assembly. Here, we present the design and synthesis of a family of perphenazine-macrocyle conjugates. We find that two-armed perphenazine-cyclam conjugates divert the monomeric form of the amyloid-β peptide away from the amyloidogenic pathway into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. This strategy prevents the formation of damaging amyloid oligomers. Kinetic analysis of the effects of these compounds on the assembly pathway, together with NMR spectroscopy, identifies rapid monomer sequestration as the underlying neuroprotective mechanism. The ability to specifically target the monomeric form of amyloid-β allows for further understanding of the impact of the multiple species formed between peptide biogenesis and plaque deposition. The modular, three-dimensional structure of these compounds provides a starting point for the design of more potent modulators of this amyloid-forming peptide, and can be adapted to probe the protein self-assembly pathways associated with other proteinopathies.Significance statementThe aggregation pathway of the amyloid-β (Aβ) peptide in Alzheimer’s disease is complex and involves multiple different species. An inability to isolate and study the impact of distinct Aβ species has undermined efforts to develop effective therapies. To address this issue, we have developed a series of molecules that specifically sequester the monomeric form of the highly aggregation-prone Aβ42 peptide. Interaction with these molecules diverts Aβ42 from the amyloidogenic pathway and prevents formation of toxic oligomeric species. We use kinetic analysis and NMR spectroscopy to identify rapid monomer sequestration as the underlying neuroprotective mechanism. Future rational development of these molecules and characterisation of their interactions with Aβ will delineate the impact of different Aβ oligomers on neurobiology and pathology.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Min-Soo Kim ◽  
Yoonhee Kim ◽  
Hyunjung Choi ◽  
Woojin Kim ◽  
Sumyung Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurofibrillary Tangles ◽  
Immune Cell ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Faecal Microbiota ◽  
Inflammatory Monocytes ◽  
The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease

2020 ◽  
Vol 78 (2) ◽  
pp. 573-585
Author(s):  
Hyemin Jang ◽  
Hee Jin Kim ◽  
Yeong Sim Choe ◽  
Soo-Jong Kim ◽  
Seongbeom Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Interaction Effect ◽  
Significant Interaction ◽  
Amyloid Β ◽  
Cognitive Change ◽  
Significant Interaction Effect ◽  
The Impact

Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

scholarly journals Pyk2 overexpression in postsynaptic neurons blocks amyloid β1–42-induced synaptotoxicity in microfluidic co-cultures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
The Impact

Abstract Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1–42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta—an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels—selectively in postsynaptic neurons is protective against amyloid β1–42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

Commentary on: L-Methylfolate, Methylcobolamine, and N-Acetylcysteine in the Treatment of Alzheimer's Disease-Related Cognitive Decline

CNS Spectrums ◽  
2010 ◽  
Vol 15 (S1) ◽  
pp. 7-7 ◽  
Author(s):  
Jeffrey L Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Methylation Status ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Vitamin B ◽  
Amyloid Β Protein ◽  
In Vivo Models ◽  
The Impact

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hey) are implicated in the pathogenesis of Alzheimer's disease (AD). They noted that Hey is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphoryalation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase β-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-β production in in vitro models; elevated Hey levels in rates are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hey levels in vitro increase amyloid-β protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hey induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

scholarly journals Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Audrey Hector ◽  
Jonathan Brouillette
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Synaptic Activity ◽  
Early Stages ◽  
The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

scholarly journals Unraveling Aβ-Mediated Multi-Pathway Calcium Dynamics in Astrocytes: Implications for Alzheimer’s Disease Treatment From Simulations

2021 ◽  
Vol 12 ◽  
Author(s):  
Langzhou Liu ◽  
Huayi Gao ◽  
Alexey Zaikin ◽  
Shangbin Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Ryanodine Receptors ◽  
Amyloid Β ◽  
Calcium Oscillations ◽  
Resting Membrane Potential ◽  
Amyloid Β Peptide ◽  
Channel Blockers ◽  
The Impact

The accumulation of amyloid β peptide (Aβ) in the brain is hypothesized to be the major factor driving Alzheimer’s disease (AD) pathogenesis. Mounting evidence suggests that astrocytes are the primary target of Aβ neurotoxicity. Aβ is known to interfere with multiple calcium fluxes, thus disrupting the calcium homeostasis regulation of astrocytes, which are likely to produce calcium oscillations. Ca2+ dyshomeostasis has been observed to precede the appearance of clinical symptoms of AD; however, it is experimentally very difficult to investigate the interactions of many mechanisms. Given that Ca2+ disruption is ubiquitously involved in AD progression, it is likely that focusing on Ca2+ dysregulation may serve as a potential therapeutic approach to preventing or treating AD, while current hypotheses concerning AD have so far failed to yield curable therapies. For this purpose, we derive and investigate a concise mathematical model for Aβ-mediated multi-pathway astrocytic intracellular Ca2+ dynamics. This model accounts for how Aβ affects various fluxes contributions through voltage-gated calcium channels, Aβ-formed channels and ryanodine receptors. Bifurcation analysis of Aβ level, which reflected the corresponding progression of the disease, revealed that Aβ significantly induced the increasing [Ca2+]i and frequency of calcium oscillations. The influence of inositol 1,4,5-trisphosphate production (IP3) is also investigated in the presence of Aβ as well as the impact of changes in resting membrane potential. In turn, the Ca2+ flux can be considerably changed by exerting specific interventions, such as ion channel blockers or receptor antagonists. By doing so, a “combination therapy” targeting multiple pathways simultaneously has finally been demonstrated to be more effective. This study helps to better understand the effect of Aβ, and our findings provide new insight into the treatment of AD.

scholarly journals Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease

2020 ◽  
Vol 21 (20) ◽  
pp. 7443 ◽  
Author(s):  
Tapan Behl ◽  
Ishnoor Kaur ◽  
Ovidiu Fratila ◽  
Roxana Brata ◽  
Simona Bungau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Agents ◽  
Active Immunotherapy ◽  
Amyloid Hypothesis ◽  
Neuronal Connections ◽  
Glucagon Like Peptide 1 ◽  
Natural Drugs ◽  
Enzymatic Pathways

One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression.

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