scholarly journals The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients

2013 ◽  
Vol 33 (8) ◽  
pp. 1251-1258 ◽  
Author(s):  
Karin Hultman ◽  
Sidney Strickland ◽  
Erin H Norris
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Apoe Genotype ◽  
Postmortem Brain ◽  
Amyloid Angiopathy ◽  
Apoe Ε4 ◽  
Cerebrovascular Dysfunction ◽  
Postmortem Brain Tissue ◽  
Clotting Protein

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.

scholarly journals An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 12 (573) ◽  
pp. eabb1206
Author(s):  
Anamitra Ghosh ◽  
Michele M. Comerota ◽  
Debin Wan ◽  
Fading Chen ◽  
Nicholas E. Propson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Small Molecule ◽  
Epoxide Hydrolase ◽  
Critical Role ◽  
Postmortem Brain ◽  
Model Of Alzheimer’S Disease ◽  
Postmortem Brain Tissue ◽  
Β Amyloid

Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD β amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.

scholarly journals Decline in verbal memory during preclinical Alzheimer's disease: Examination of the effect of APOE genotype

2002 ◽  
Vol 8 (7) ◽  
pp. 943-955 ◽  
Author(s):  
KELLY L. LANGE ◽  
MARK W. BONDI ◽  
DAVID P. SALMON ◽  
DOUGLAS GALASKO ◽  
DEAN C. DELIS ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Episodic Memory ◽  
Verbal Memory ◽  
Verbal Learning ◽  
Apoe Genotype ◽  
Apoe Ε4 ◽  
Dementia Syndrome ◽  
Ε4 Allele

A subtle decline in episodic memory often occurs prior to the emergence of the full dementia syndrome in nondemented older adults who develop Alzheimer's disease (AD). The APOE-ε4 genotype may engender a more virulent form of AD that hastens this decline. To examine this possibility, we compared the rate of decline in episodic memory during the preclinical phase of AD in individuals with or without at least one APOE ε4 allele. Nondemented normal control (NC; n = 84) participants, nondemented older adults who subsequently developed dementia within 1 or 2 years (i.e., preclinical AD; n = 20), and patients with mild AD (n = 53) were examined with 2 commonly employed tests of episodic memory, the Logical Memory subtest of the Wechsler Memory Scale–Revised and the California Verbal Learning Test. Results revealed a precipitous decline in verbal memory abilities 1 to 2 years prior to the onset of the dementia syndrome, but there was little effect of APOE genotype on the rate of this memory decline. The presence of an APOE-ε4 allele, however, did have a differential effect on the sensitivity of the 2 types of memory tests for tracking progression and made an independent contribution to the prediction of conversion to AD. (JINS, 2002, 8, 943–955.)

Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s Disease

2018 ◽  
Vol 15 (10) ◽  
pp. 938-950 ◽  
Author(s):  
Martina Zverova ◽  
Eva Kitzlerova ◽  
Zdenek Fisar ◽  
Roman Jirak ◽  
Jana Hroudova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Apoe Genotype ◽  
Plasma Biomarkers ◽  
Plasma Melatonin ◽  
Apoe Ε4 ◽  
Ε4 Allele ◽  
Severity Of Dementia

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

scholarly journals Interleukinų IL1A ir IL6 genų polimorfizmas: sąsajų su APOE genotipu ir sporadinės Alzheimerio ligos klinikine eiga paieška Interleukin IL1a and IL6 gene polymorphism: search for association with APOE genotype and clinical course of sporadic Alzheimer’s disease

2020 ◽  
Vol 23 (81) ◽  
pp. 130-139
Author(s):  
G. Pšemeneckienė ◽  
K. Petrikonis ◽  
D. Rastenytė
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Polymorphism ◽  
Clinical Course ◽  
Apoe Genotype ◽  
Sporadic Alzheimer’S Disease ◽  
Apoe Ε4 ◽  
Il6 Gene

Įvadas. Yra duomenų, kad IL1α ir IL6, kaip vienų svarbiausių citokinų, dalyvaujančių neurouždegimo procesuose, genų polimorfizmai yra susiję su Alzheimerio ligos (AL) rizika. Šiame tyrime siekėme įvertinti IL1A -889C>T ir IL6 -174G>C polimorfizmų sąsajas su sporadinės AL rizika APOE ε4 nešiotojams ir APOE rizikos alelio neturintiems asmenims. Taip pat tyrėme IL1A -889C>T ir IL6 -174G>C polimorfizmų sąsajas su AL progresavimo pobūdžiu. Tiriamieji ir tyrimo metodai. Tyrime dalyvavo 110 sergančiųjų sporadine AL ir 115 sutapatintų pagal amžių ir lytį sveikų kontrolinių tiriamųjų, kurių pažinimo funkcijos nesutrikusios (Lietuvos populiacija). IL1A -889C>T (rs1800587) ir IL6 -174G>C (rs1800795, Intro- no tipo) genotipavimas atliktas tikro laiko PGR (TL-PGR) metodu. Rezultatai. IL1A -889C>T genotipų dažniai APOE4+ grupėje (C/C – 52,9 %, C/T – 41,2 %, T/T – 5,9 %), lyginant su APOE4- sergančiaisiais AL (C/C – 55,6 %, C/T – 37,0 %, T/T – 7,4 %), nesiskyrė (p = 0,887). Sergantiems AL pacientams IL6 -174G>C genotipai APOE4+ grupėje (G/G – 11,8 %, G/C – 62,7 %, C/C – 25,5 %) ir APOE4- grupėje (G/G – 14,8 %, G/C – 61,1 %, C/C – 24,1 %) buvo pasiskirstę panašiai (p = 0,898). Genotipų dažniai reikšmingai nesiskyrė sergantiesiems greitai progresuojančia AL, lyginant su lėtai progresuojančia AL (p (IL1A -889C>T) = 0,638; p (IL6 -174G>C) = 0,118). IL1A -889C>T ir IL6 -174G>C polimorfizmų paveldėjimas (dominantinio, overdominantinio ir recesyvinio modeli0), atsižvelgiant į APOE genotipą, reikšmingai nekeitė galimybių santykio sirgti AL (p < 0,05). Lėtai ir greitai progresuojančios AL grupėse IL1A -889C>T ir IL6 -174G>C polimorfizmų paveldėjimas AL galimybei reikšmingos įtakos neturėjo (p < 0,05). Išvados. IL1A -889C>T ir IL6 -174G>C genotipų pasiskirstymas grupėse pagal APOE ε4 ir grupėse pagal AL progresavimo pobūdį reikšmingai nesiskyrė. Reikšmingų IL1A -889C>T ir IL6 -174G>C polimorfizmų sąsajų su AL rizika nei APOE4+, nei APOE4- tiriamiesiems nenustatyta. Mūsų duomenimis, IL1A -889C>T ir IL6 -174G>C polimorfizmų paveldėjimas nesusijęs su spartesniu AL progresavimu.

Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease

2010 ◽  
Vol 120 (2) ◽  
pp. 169-183 ◽  
Author(s):  
Dietmar Rudolf Thal ◽  
Andreas Papassotiropoulos ◽  
Takaomi C. Saido ◽  
W. Sue T. Griffin ◽  
Robert E. Mrak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Angiopathy ◽  
Sporadic Alzheimer’S Disease ◽  
Apoe Ε4 ◽  
Cerebral Amyloid

scholarly journals proNGF Measurement in Cerebrospinal Fluid Samples of a Large Cohort of Living Patients With Alzheimer's Disease by a New Automated Immunoassay

2021 ◽  
Vol 13 ◽  
Author(s):  
Francesca Malerba ◽  
Ivan Arisi ◽  
Rita Florio ◽  
Chiara Zecca ◽  
Maria Teresa Dell'Abate ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Molecular Size ◽  
Fold Increase ◽  
Postmortem Brain ◽  
Subjective Memory ◽  
Postmortem Brain Tissue ◽  
Significant Difference ◽  
New Biomarkers

The discovery of new biomarkers for Alzheimer's disease (AD) is essential for an accurate diagnosis, to conceive new strategies of treatments, and for monitoring the efficacy of potential disease-modifying therapies in clinical trials. proNGF levels in the cerebrospinal fluid (CSF) represent a promising diagnostic biomarker for AD, but its validation was hampered by the absence of a reliable immunoassay. In the literature, proNGF is currently measured in postmortem brain tissue by semiquantitative immunoblot. Here we describe the development and validation of a new method to measure proNGF in the CSF of living patients. This method, based on molecular size separation by capillary electrophoresis, is automated and shows a 40-fold increase in sensitivity with respect to the proNGF immunoblot, largely used in literature, and is robust, specific, and scalable to high-throughput. We have measured proNGF in the cerebrospinal fluid of 84 living patients with AD, 13 controls, and 15 subjective memory complaints (SMC) subjects. By comparing the proNGF levels in the three groups, we found a very significant difference between proNGF levels in AD samples compared with both controls and SMC subjects, while no significant difference was found between SMC and controls. Because of the development of this new immunoassay, we are ready to explore the potentiality of proNGF as a new biomarker for AD or subgroups thereof, as well as for other neurodegenerative diseases.

scholarly journals Failure To Detect Chlamydia pneumoniaein the Late-Onset Alzheimer's Brain

2000 ◽  
Vol 38 (7) ◽  
pp. 2591-2594 ◽  
Author(s):  
Robert H. Ring ◽  
Joseph M. Lyons
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chlamydia Pneumoniae ◽  
Late Onset ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Respiratory Pathogen ◽  
Specific Gene ◽  
Tissue Samples ◽  
Postmortem Brain Tissue

Epidemiological studies have yet to identify a single cause for the most common late-onset form of Alzheimer's disease. The common respiratory pathogen Chlamydia pneumoniae recently has been implicated as a risk factor for this form of Alzheimer's disease. Were this true, there would be a dramatic shift in current paradigms of Alzheimer's disease research and treatment. In the absence of published confirmation, we obtained postmortem brain tissue from late-onset Alzheimer's disease patients (n = 15) and representative controls (n = 5) and extracted DNA from up to six separate brain regions in each instance, including those areas particularly relevant to Alzheimer's disease neuropathology. Each sample of DNA (n = 101) was assayed five times or more for the presence of C. pneumoniae DNA using a nested-PCR protocol targeting a species-specific gene sequence coding for the major outer membrane protein of this organism. We were unable unequivocally to detect C. pneumoniae in any of the 101 samples tested by PCR and failed to culture the organism from tissue samples. We conclude that C. pneumoniae is neither strongly nor uniquely associated with the neuropathology seen in late-onset Alzheimer's disease.

scholarly journals Cerebrovascular and microglial states are not altered by functional neuroinflammatory gene variant

2016 ◽  
Vol 36 (4) ◽  
pp. 819-830 ◽  
Author(s):  
Daniel Felsky ◽  
Philip L De Jager ◽  
Julie A Schneider ◽  
Konstantinos Arfanakis ◽  
Debra A Fleischman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Protein A ◽  
Translocator Protein ◽  
Postmortem Brain ◽  
Amyloid Angiopathy ◽  
Religious Orders ◽  
Binding Characteristics

The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer’s disease, which is characterized by alterations in vascular and inflammatory states. A TSPO variant, rs6971, determines binding affinity of exogenous radioligands in vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer’s Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation. We found that rs6971 does not alter translocator protein in a way that impacts cerebrovascular and inflammatory states known to be affected in dementia.

scholarly journals The Association between Polygenic Hazard and Markers of Alzheimer’s Disease Following Stratification for APOE Genotype

2020 ◽  
Vol 17 (7) ◽  
pp. 667-679
Author(s):  
Matteo De Marco ◽  
Riccardo Manca ◽  
Janine Kirby ◽  
Guillaume M. Hautbergue ◽  
Daniel J. Blackburn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Functioning ◽  
Grey Matter ◽  
Linear Models ◽  
Apoe Genotype ◽  
Apoe Ε4 ◽  
Allele Status ◽  
Ε4 Allele ◽  
Clinical Profiles

Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles. Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. Methods: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer’s Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. Results: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants. Conclusion: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

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