scholarly journals Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

2020 ◽  
Vol 77 (2) ◽  
pp. 675-688
Author(s):  
Susan Fung ◽  
Carole L. Smith ◽  
Katherine E. Prater ◽  
Amanda Case ◽  
Kevin Green ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Early Onset ◽  
Amyloid Β ◽  
Innate Immune ◽  
Cellular Functions ◽  
Branch Number ◽  
Inflammatory Stimuli ◽  
Familial Alzheimer Disease ◽  
Disease Variant

Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aβ internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production.

scholarly journals In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid β-peptide of APP

2010 ◽  
Vol 48 (1) ◽  
pp. 136-144 ◽  
Author(s):  
D. Allan Butterfield ◽  
Veronica Galvan ◽  
Miranda Bader Lange ◽  
Huidong Tang ◽  
Renã A. Sowell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Methionine 35

scholarly journals Modeling the β secretase cleavage site and humanizing Amyloid-Beta Precursor Protein in rat and mouse to study Alzheimer Disease.

2020 ◽  
Author(s):  
Lutgarde Serneels ◽  
Dries T'Syen ◽  
Laura Perez-Benito ◽  
Tom Theys ◽  
Bart De Strooper
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Alzheimer Disease ◽  
Early Onset ◽  
Computational Modelling ◽  
Original Strain ◽  
Rodent Models ◽  
App Processing

Abstract Background Three amino acid differences between rodent and human APP affect medically important features including β-secretase cleavage of APP and aggregation of the Aβ peptide(1–3). Most rodent models for Alzheimer’s disease (AD) are therefore based on the human APP sequence expressed from artificial mini-genes randomly inserted in the rodent genome. While these models mimic rather well biochemical aspects of the disease such as Aβ-aggregation, they are also prone to overexpression artifacts and to complex phenotypical alterations due to genes affected in or close to the insertion sites of the mini-genes(4,5). Knock-in strategies introducing clinical mutants in a humanized endogenous rodent APP sequence(6) represent useful improvements, but need to be compared with appropriate humanized wild type (WT) mice.Methods Computational modelling of the human β-CTF bound to BACE1 was used to study the differential processing of rodent and human APP. We humanized the three pivotal residues G676R, F681Y and R684H (labeled according to the human APP770 isoform) in the mouse as well as in the rat by a CRISPR-Cas9 approach. These new models, termed mouse and rat App hu/hu , express APP from the endogenous promotor. We also introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene.Results We show that the three amino acid substitutions in the rodent sequence lower the affinity of APP substrate for BACE1 cleavage. The effect on β-secretase processing was confirmed as both humanized rodent models produce three times more (human) Aβ compared to their WT rodent original strain. These models represent suitable controls or starting points for studying the effect of transgenes or knock-in mutations on APP processing(6). We introduced the early-onset familial Alzheimer disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene and provide an initial characterization of Aβ processing in this novel rat AD model.Conclusion The different humanized APP models (rat and mouse) expressing human Aβ and PSEN1 M139T are valuable controls to study APP processing in vivo and allow to implement the use of human Aβ Elisa which is more sensitive than their rodent counterpart. These animals will be made available to the research community.

scholarly journals Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-β Proteins: Phantom Study

2018 ◽  
Vol 9 ◽  
pp. 117959721878108 ◽  
Author(s):  
David Tes ◽  
Karl Kratkiewicz ◽  
Ahmed Aber ◽  
Luke Horton ◽  
Mohsin Zafar ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Amyloid Β ◽  
The United States ◽  
Fluorescent Imaging ◽  
Fluorescent Properties ◽  
In Vivo Experiments ◽  
The Brain

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-β (Aβ), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aβ proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aβ biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.

scholarly journals Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes

2007 ◽  
Vol 16 (21) ◽  
pp. 2626-2639 ◽  
Author(s):  
A. Li ◽  
Z. Xie ◽  
Y. Dong ◽  
K. M. McKay ◽  
M. L. McKee ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Early Onset ◽  
Disease Genes ◽  
Isolation And Characterization

scholarly journals The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Aβ Fibril Formation without Increasing Protofibril Formation

2006 ◽  
Vol 282 (7) ◽  
pp. 4916-4923 ◽  
Author(s):  
Yukiko Hori ◽  
Tadafumi Hashimoto ◽  
Yosuke Wakutani ◽  
Katsuya Urakami ◽  
Kenji Nakashima ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Amyloid Fibril Formation ◽  
Β Protein ◽  
Familial Alzheimer Disease ◽  
Aβ Production

A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.

scholarly journals Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tissue Atrophy in Early Alzheimer Disease

2021 ◽  
Author(s):  
Satya V.V.N. Kothapalli ◽  
Tammie L. Benzinger ◽  
Andrew. J. Aschenbrenner ◽  
Richard. J. Perrin ◽  
Charles. F. Hildebolt ◽  
...  
Keyword(s):  
Dark Matter ◽  
Alzheimer Disease ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Imaging Biomarker ◽  
Control Group ◽  
Histopathological Study ◽  
In Vivo Evaluation ◽  
Preclinical Ad

AbstractBackgroundCurrently, brain tissue atrophy serves as in vivo MRI biomarker of neurodegeneration in Alzheimer Disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis.ObjectiveTo apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus.MethodsSeventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®)=0, amyloid β (Aβ)-negative), n=34]; Preclinical AD (CDR=0, Aβ-positive, n=19); and mild AD (CDR=0.5 or 1, Aβ-positive, n=17).ResultsIn hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, the other, with relatively preserved neurons - “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group - neuronal loss ranged between 31% and 43% while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration.Conclusionin vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

scholarly journals Covalent Protein Painting Reveals Structural Changes in the Proteome in Alzheimer Disease

2020 ◽  
Author(s):  
Casimir Bamberger ◽  
Sandra Pankow ◽  
Salvador Martínez-Bartolomé ◽  
Michelle Ma ◽  
Jolene Diedrich ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Chemical Modification ◽  
Succinate Dehydrogenase ◽  
Structural Changes ◽  
Amyloid Β ◽  
Lewy Body Disease ◽  
Structural Proteomics ◽  
Amyloid Β Peptide ◽  
Lysine Residues

AbstractThe 3D structures of aberrant protein folds have been visualized in exquisite detail, yet no method has been able to quantitatively measure protein misfolding across a proteome. Here, we present Covalent Protein Painting (CPP), a mass spectrometry-based structural proteomics approach to quantify the accessibility of lysine ε-amines for chemical modification at the surface of natively folded proteins. We used CPP to survey 2,645 lysine residues in the proteome of HEK293T cells in vivo and found that mild heat shock increased rather than decreased lysine accessibility for chemical modification. CPP was able to differentiate patients with Alzheimer disease (AD) or Lewy body disease (LBD) or both from controls based on relative accessibility of lysine residues K147, K137, and K28 in Tubulin-β, Succinate dehydrogenase, and amyloid-β peptide, respectively. The alterations of Tubulin-β and Succinate dehydrogenase hint to broader perturbations of the proteome in AD beyond amyloid-β and hyper-phosphorylated tau.

scholarly journals CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem

2018 ◽  
Vol 4 (1) ◽  
pp. e216 ◽  
Author(s):  
Andréa L. Benedet ◽  
Lei Yu ◽  
Aurélie Labbe ◽  
Sulantha Mathotaarachchi ◽  
Tharick A. Pascoal ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Protective Factor ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Candidate Gene Approach ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Postmortem Brains ◽  
Global Cognition

ObjectiveTo verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts.MethodsA candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts.ResultsAnalysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ.ConclusionsTogether, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.

Increased presence of amino-terminally-truncated Aβ-peptides in presenilin 1 early-onset familial Alzheimer disease

2000 ◽  
Vol 21 ◽  
pp. 194
Author(s):  
Claudio Russo ◽  
Takaomi C. Saido ◽  
Christine Hulette ◽  
Kathleen Price ◽  
Bernardino Ghetti ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Early Onset ◽  
Presenilin 1 ◽  
Aβ Peptides ◽  
Familial Alzheimer Disease
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