Apolipoprotein E and beta A4-amyloid: signals and effects.
In humans, the apolipoprotein E gene (APOE) is polymorphic with the alleles APOE epsilon 2, 3 and 4 coding for apolipoproteins (Apo) E2, 3 and 4. Apart from age, the APOE epsilon 4 allele represents the most important risk factor in sporadic Alzheimer's disease (AD). Compared to APOE epsilon 3 homozygotes, the histopathological onset of tau pathology is found 1-2 decades earlier but progresses with the same speed. ApoE dose-dependently and specifically increases free intraneuronal calcium levels in the order ApoE4 > ApoE3 > ApoE2. This effect is amplified in the presence of beta A4-peptide. The ApoE effects on calcium are not affected by the blockade of action potentials with tetrodotoxin, or by inhibition of common ApoE binding sites. The calcium channel involved has been identified as a P/Q-type-like channel. Brain tissue ApoE levels differ with respect to APOE alleles and Braak-stage for Alzheimer-histopathology. The production of ApoE in astrocytes is controlled by several receptor/effector systems such as adrenoceptors and cAMP. In the presence of beta A4-peptide fragments, astrocytes stop their synthesis of ApoE resulting in a massive reduction in the bioavailability of ApoE. In the periphery, ApoE directs cholesterol transport and thereby influences its cellular concentrations. In neurons, changes in the concentration of cholesterol influence the phosphorylation status of the microtubule-associated protein tau at sites known to be altered in AD.
Ohm
T G
TG
Institute fur Anatomie, University Klinikum Charité, D-10098 Berlin, Germany.
Hamker
U
U
Cedazo-Minguez
A
A
Röckl
W
W
Scharnagl
H
H
März
W
W
Cowburn
R
R
Müller
W
W
Meske
V
V
D000483:Alleles; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D002784:Cholesterol