Apolipoprotein E4 promotes the early deposition of Aβ42 and then Aβ40 in the elderly

Abstract

The apolipoprotein Eepsilon4 allele (ApoEepsilon4) is associated with a selective increase in deposition of the 40-amino acid form of the beta-amyloid peptide (Abeta40) in endstage Alzheimer's disease. To determine how apoE genotype affects the early events in beta-amyloid pathogenesis, we analyzed the medial temporal lobes of 244 elderly persons who were not clinically demented using antibodies selective for the C termini of Abeta40 and Abeta42. We found that: (1) the number of both Abeta42- and Abeta40-positive senile plaques increase with age; (2) Abeta42 appears at younger ages, and in more amyloid deposits, than does Abeta40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoEepsilon4 are more likely to have Abeta42- and Abeta40-immunoreactive deposits than are persons without ApoEepsilon4; (4) Abeta40-containing plaques arise at least a decade later than do Abeta42 plaques, and are seldom found in the medial temporal lobe of older persons lacking ApoEepsilon4; and (5) in the absence of overt Alzheimer's disease, cerebral amyloid angiopathy is rare in the elderly, but in our sample was significantly augmented in ApoEepsilon4 homozygotes. We conclude that ApoEepsilon4 hastens the onset of Abeta42 deposition in the senescent brain, which in turn fosters the earlier evolution of fibrillar, Abeta40-positive plaques, thereby increasing the risk of Alzheimer's disease.

Label-free detection of ApoE4-mediated β-amyloid aggregation on single nanoparticle uncovering Alzheimer's disease

“…2C), since ApoE4 promotes Aβ42 changing conformation to stickier β-amyloids which are self-assembled into the matrix under processes of transformation of the β-amyloids to fibrils and the fraction and formation of the dense Holtzman et al, 2000). This result of deposition of amyloid fibrils is a crucial step in the development of AD (Walker et al, 2000). Furthermore, in the presence of ApoE4, only Aβ42 peptide, not Aβ40, was aggregated, showing that ApoE4 increases Aβ42 aggregation, which is in line with other previous reports (Zepa et al, 2011).…”

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

“…An important role for apoE in determining brain A␤ burden in vivo has been established and numerous studies have documented an increase in brain A␤ burden in AD patients who are 4 carriers Walker et al, 2000;DeMattos, 2004). Previous studies from our laboratory used PDAPP mice that were crossed to transgenic mice expressing human apoE exclusively in astrocytes (Fagan et al, 2002).…”

Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease

“…Individuals carrying one or two 4 alleles develop AD at a younger age and have higher amyloid-plaque burden compared with individuals carrying two 3 alleles (5-8). In fact, several studies have demonstrated higher brain A␤ burden in elderly nondemented individuals carrying one or two 4 alleles, suggesting that apoE4 somehow contributes to A␤ deposition and brain amyloid burden (9,10). Genetic epidemiological studies also suggest a protective role for the 2 allele, which in some studies has been shown to reduce the risk of AD by Ϸ50% (11).…”