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

2013 ◽  
Vol 38 (4) ◽  
pp. 831-844 ◽  
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

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 Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

scholarly journals Cerebral artery dilation during transient ischemia is impaired by amyloid β deposition around the cerebral artery in Alzheimer’s disease model mice

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
Nobuhiro Watanabe ◽  
Yoshihiro Noda ◽  
Taeko Nemoto ◽  
Kaori Iimura ◽  
Takahiko Shimizu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Artery ◽  
Disease Model ◽  
Amyloid Β ◽  
Wild Type ◽  
Transient Ischemia ◽  
Basal Diameter ◽  
Two Photon Microscopy ◽  
Pial Artery

AbstractTransient ischemia is an exacerbation factor of Alzheimer’s disease (AD). We aimed to examine the influence of amyloid β (Aβ) deposition around the cerebral (pial) artery in terms of diameter changes in the cerebral artery during transient ischemia in AD model mice (APPNL-G-F) under urethane anesthesia. Cerebral vasculature and Aβ deposition were examined using two-photon microscopy. Cerebral ischemia was induced by transient occlusion of the unilateral common carotid artery. The diameter of the pial artery was quantitatively measured. In wild-type mice, the diameter of arteries increased during occlusion and returned to their basal diameter after re-opening. In AD model mice, the artery response during occlusion differed depending on Aβ deposition sites. Arterial diameter changes at non-Aβ deposition site were similar to those in wild-type mice, whereas they were significantly smaller at Aβ deposition site. The results suggest that cerebral artery changes during ischemia are impaired by Aβ deposition.

scholarly journals PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

2016 ◽  
Vol 113 (43) ◽  
pp. 12292-12297 ◽  
Author(s):  
Loukia Katsouri ◽  
Yau M. Lim ◽  
Katrin Blondrath ◽  
Ioanna Eleftheriadou ◽  
Laura Lombardero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Lentiviral Vector ◽  
Disease Model ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects ◽  
Peroxisome Proliferator Activated Receptor

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-β in an Alzheimer’s Disease Model

2020 ◽  
Vol 142 (52) ◽  
pp. 21702-21711
Author(s):  
Mengmeng Ma ◽  
Zhenqi Liu ◽  
Nan Gao ◽  
Zifeng Pi ◽  
Xiubo Du ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Model ◽  
Amyloid Β

Hybrid FMT–CT imaging of amyloid-β plaques in a murine Alzheimer's disease model

NeuroImage ◽  
2009 ◽  
Vol 44 (4) ◽  
pp. 1304-1311 ◽  
Author(s):  
D HYDE ◽  
R DEKLEINE ◽  
S MACLAURIN ◽  
E MILLER ◽  
D BROOKS ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Model ◽  
Amyloid Β ◽  
Ct Imaging

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.

Tyrosol Reduces Amyloid-β Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer’s Disease Model Mice

2019 ◽  
Vol 70 (3) ◽  
pp. 937-952 ◽  
Author(s):  
Kaori Taniguchi ◽  
Fumiko Yamamoto ◽  
Takuya Arai ◽  
Jinwei Yang ◽  
Yusuke Sakai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Model ◽  
Amyloid Β ◽  
Cognitive Disturbances
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