Model of Genetic Susceptibility to Late-Onset Alzheimer’s Disease: Mice Transgenic for Human Apolipoprotein E Alleles

1999 ◽  
pp. 215-243
Author(s):  
Donald E. Schmechel ◽  
Pu-Ting Xu ◽  
John R. Gilbert ◽  
Allen D. Roses
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Genetic Susceptibility ◽  
Late Onset ◽  
Human Apolipoprotein

scholarly journals Hidden Aggregation Hot-Spots on Human Apolipoprotein E: A Structural Study

2019 ◽  
Vol 20 (9) ◽  
pp. 2274 ◽  
Author(s):  
Paraskevi L. Tsiolaki ◽  
Aikaterini D. Katsafana ◽  
Fotis A. Baltoumas ◽  
Nikolaos N. Louros ◽  
Vassiliki A. Iconomidou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Plasma Cholesterol ◽  
Human Apolipoprotein ◽  
Computational Work ◽  
Peptide Analogues ◽  
Experimental Level

Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aβ peptide in amyloid plaques in Alzheimer’s disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer’s disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE–Αβ complex. Our in vitro biophysical results prove that apoE peptide–analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE–Αβ complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αβ; taking an important step forward in the field of Alzheimer’s anti-aggregation drug development.

A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease

1999 ◽  
Vol 263 (2-3) ◽  
pp. 129-132 ◽  
Author(s):  
M.Ilyas Kamboh ◽  
Christopher E Aston ◽  
Jordi Perez-Tur ◽  
Emre Kokmen ◽  
Robert E Ferrell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Novel Mutation ◽  
E Gene ◽  
Apolipoprotein E Gene

scholarly journals Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

1995 ◽  
Vol 306 (2) ◽  
pp. 599-604 ◽  
Author(s):  
E M Castano ◽  
F Prelli ◽  
T Wisniewski ◽  
A Golabek ◽  
R A Kumar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Tau Proteins ◽  
Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

Apolipoprotein E promoter and α2-Macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer's disease

1999 ◽  
Vol 269 (3) ◽  
pp. 173-177 ◽  
Author(s):  
Lan Chen ◽  
Larry Baum ◽  
Ho-Keung Ng ◽  
Lisa Y.S Chan ◽  
Isabel Sastre ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Α2 Macroglobulin

scholarly journals Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

2003 ◽  
Vol 162 (1) ◽  
pp. 313-319 ◽  
Author(s):  
David G. Cook ◽  
James B. Leverenz ◽  
Pamela J. McMillan ◽  
J. Jacob Kulstad ◽  
Sasha Ericksen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Ε4 Allele

Confirmation of the  4 allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer's disease

Neurology ◽  
1994 ◽  
Vol 44 (2) ◽  
pp. 342-342 ◽  
Author(s):  
T. Brousseau ◽  
S. Legrain ◽  
C. Berr ◽  
V. Gourlet ◽  
O. Vidal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Apolipoprotein E ◽  
Late Onset ◽  
E Gene ◽  
Apolipoprotein E Gene

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

2022 ◽  
pp. 0271678X2110690
Author(s):  
Charles E Seaks ◽  
Erica M Weekman ◽  
Tiffany L Sudduth ◽  
Kevin Xie ◽  
Brandi Wasek ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Apoe Ε4 ◽  
Perivascular Inflammation ◽  
Ε4 Allele ◽  
Barrier Breakdown ◽  
The Impact

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

scholarly journals Association of apolipoprotein E allele  4 with late-onset familial and sporadic Alzheimer's disease

Neurology ◽  
2011 ◽  
Vol 77 (10) ◽  
pp. 950-950 ◽  
Author(s):  
A. M. Saunders ◽  
W. J. Strittmatter ◽  
D. Schmechel ◽  
P. H. St. George-Hyslop ◽  
M. A. Pericak-Vance ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Sporadic Alzheimer’S Disease
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