scholarly journals Investigating the role of APOE: limitations of human pluripotent stem cell-derived cerebral organoids

2020 ◽  
Author(s):  
Damián Hernández ◽  
Louise A. Rooney ◽  
Maciej Daniszewski ◽  
Lerna Gulluyan ◽  
Helena H. Liang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Line ◽  
Human Fibroblasts ◽  
Susceptibility Gene ◽  
Tau Phosphorylation ◽  
Isogenic Lines ◽  
Apoe Ε4 ◽  
Increased Risk ◽  
Β Amyloid

SummaryApolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease, with the presence of APOE-ε4 associated with increased risk of developing Alzheimer’s disease. Here, we reprogrammed human fibroblasts from individuals with different APOE-ε genotypes into induced pluripotent stem cells, and generated isogenic lines with different APOE profiles. We then differentiated these into cerebral organoids for six months and assessed the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified intra- and inter-variabilities in the organoids’ cell composition. Using the CRISPR-edited APOE isogenic lines, we observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau between the isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the batch-to-batch and cell-line-to-cell-line variabilities need to be considered when using cerebral organoids.

scholarly journals Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2713-2722 ◽  
Author(s):  
Jenna C. Carroll ◽  
Emily R. Rosario ◽  
Angela Villamagna ◽  
Christian J. Pike
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Postmenopausal Women ◽  
Transgenic Mouse Model ◽  
Dependent Behavior ◽  
Potential Efficacy ◽  
Increased Risk ◽  
Neural Interactions ◽  
Β Amyloid ◽  
Insight Into

Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer’s disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E2). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E2 in ovariectomized 3×Tg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3×Tg-AD mice, including accumulation of β-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E2 treatment alone prevents the increases in pathology. Continuous progesterone did not affect β-amyloid levels when delivered alone but blocked the Aβ-lowering action of E2. In contrast, cyclic progesterone significantly reduced β-amyloid levels by itself and enhanced rather than inhibited the E2 effects. These results provide new insight into the neural interactions between E2 and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

scholarly journals The clinical utility of gene testing for Alzheimer’s disease

2011 ◽  
Vol 3 (1) ◽  
pp. 1 ◽  
Author(s):  
Emily R. Atkins ◽  
Peter K. Panegyres
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Late Onset ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Genome Wide Association Studies ◽  
Apoe Ε4 ◽  
Gene Testing ◽  
A Genome

Alzheimer’s disease (AD) is the largest cause of dementia, affecting 35.6 million people in 2010. Amyloid precursor protein, presenilin 1 and presenilin 2 mutations are known to cause familial early-onset AD, whereas apolipoprotein E (APOE) ε4 is a susceptibility gene for late-onset AD. The genes for phosphatidylinositol- binding clathrin assembly protein, clusterin and complement receptor 1 have recently been described by genome-wide association studies as potential risk factors for lateonset AD. Also, a genome association study using single neucleotide polymorphisms has identified an association of neuronal sortilin related receptor and late-onset AD. Gene testing, and also predictive gene testing, may be of benefit in suspected familial early-onset AD however it adds little to the diagnosis of lateonset AD and does not alter the treatment. We do not recommend APOE ε4 genotyping.

Effects of Acetylcholine on β-Amyloid-Induced cPLA2 Activation in the TB Neuroectodermal Cell Line: Implications for the Pathogenesis of Alzheimer’s Disease

2017 ◽  
Vol 38 (4) ◽  
pp. 817-826 ◽  
Author(s):  
Arianna Polverino ◽  
Manuela Grimaldi ◽  
Pierpaolo Sorrentino ◽  
Francesca Jacini ◽  
Anna Maria D’Ursi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Line ◽  
Cpla2 Activation ◽  
Β Amyloid

Soluble β-amyloid induces Alzheimer's disease features in human fibroblasts and in neuronal tissues

Life Sciences ◽  
1996 ◽  
Vol 59 (5-6) ◽  
pp. 491-498 ◽  
Author(s):  
René Etcheberrigaray ◽  
Jennifer L. Payne ◽  
Daniel L. Alkon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Fibroblasts ◽  
Neuronal Tissues ◽  
Β Amyloid

scholarly journals Plasma neurofilament light as a longitudinal biomarker of neurodegeneration in Alzheimer’s disease

2019 ◽  
Vol 5 (2) ◽  
pp. 94-105 ◽  
Author(s):  
Ya-Nan Ou ◽  
Hao Hu ◽  
Zuo-Teng Wang ◽  
Wei Xu ◽  
Lan Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Rate Of Change ◽  
Neurofilament Light ◽  
Cox Proportional Hazards Models ◽  
Increased Risk ◽  
Β Amyloid ◽  
Longitudinal Biomarker

Objective: To examine whether plasma neurofilament light (NFL) might be a potential longitudinal biomarker for Alzheimer’s disease (AD). Methods: A total of 835 individuals from the Alzheimer’s Disease Neuroimaging Initiative were involved. Correlations of the rate of change in plasma NFL with cerebrospinal fluid biomarkers, cognition, and brain structure were investigated. Cox proportional hazards models were used to assess the associations between quartiles of plasma NFL and the risk of AD conversion. Results: Participants were further divided into β amyloid-positive (Aβ+) versus β amyloid-negative (Aβ−), resulting in five biomarker group combinations, which are CN Aβ−, CN Aβ+, MCI Aβ−, MCI Aβ+ and AD Aβ+. Plasma NFL concentration markedly increased in the five groups longitudinally ( p < 0.001) with the greatest rate of change in AD Aβ+ group. The rate of change in plasma NFL was associated with cognitive deficits and neuroimaging hallmarks of AD over time ( p < 0.005). Compared with the bottom quartile, the top quartile of change rate was associated with a 5.41-fold increased risk of AD (95% CI = 1.83−16.01) in the multivariate model. Conclusion: Our finding implies the potential of plasma NFL as a longitudinal noninvasive biomarker in AD.

scholarly journals Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?

2016 ◽  
Vol 213 (8) ◽  
pp. 1375-1385 ◽  
Author(s):  
Molly Stanley ◽  
Shannon L. Macauley ◽  
David M. Holtzman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Intranasal Insulin ◽  
Increased Risk ◽  
High Insulin ◽  
Neuronal Insulin Resistance

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD.

Risk of Dementia in Posttraumatic Stress Disorder

2020 ◽  
pp. 089198872095708
Author(s):  
Alby Elias ◽  
Christopher Rowe ◽  
Malcolm Hopwood
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Posttraumatic Stress Disorder ◽  
Posttraumatic Stress ◽  
Vietnam Veterans ◽  
Stress Disorder ◽  
Convincing Evidence ◽  
Dementia Syndrome ◽  
Increased Risk ◽  
Β Amyloid

Several studies have investigated the risk of dementia in posttraumatic stress disorder (PTSD) using a varying methodology. Epidemiological studies have found an increased risk of dementia with PTSD in Vietnam veterans as well as the general population. Laboratory studies reported the accelerated formation of β-amyloid and tau, which represent the primary pathology of Alzheimer’s dementia in animal models of PTSD. These investigations were conducted against a background of cognitive impairment and atrophy of the hippocampus and certain cortical areas in patients with PTSD. Very few studies have investigated the pathological basis in humans for the reported association of PTSD with dementia. This important gap in the literature has recently been partly addressed by very few studies that estimated the burden of β-amyloid and tau. The PET studies did not show an association between PTSD and the specific pathology of Alzheimer’s disease or signs of neurodegenerative diseases underlying other dementia syndromes. Another study demonstrated decreased plasma β-amyloid load and increased plasma β-amyloid 42/40 ratio in PTSD without PET evaluation. While PTSD is associated with an increased risk of dementia syndrome in general, there is no convincing evidence that it causes or accelerates the pathology of Alzheimer’s disease, which causes the most common type of dementia. Factors that may account for the association between PTSD and a clinical diagnosis of dementia are discussed in this review.

scholarly journals β-Amyloid is Associated with Aberrant Metabolic Connectivity in Subjects with Mild Cognitive Impairment

2014 ◽  
Vol 34 (7) ◽  
pp. 1169-1179 ◽  
Author(s):  
Felix Carbonell ◽  
Arnaud Charil ◽  
Alex P Zijdenbos ◽  
Alan C Evans ◽  
Barry J Bedell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Disease Process ◽  
Brain Regions ◽  
Apoe Ε4 ◽  
Positron Emission ◽  
Β Amyloid ◽  
Glucose Hypometabolism

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein ε4 (APOE ε4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ε4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ε4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.

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