Influence of APOE genotype and the presence of Alzheimer's pathology on synaptic membrane lipids of human brains

Abstract

The APOE genotype is the major risk factor for Alzheimer's disease (AD); however, it remains unclarified how the ε4 allele accelerates whereas the ε2 allele suppresses AD development, compared with the more common ε3 allele. On the basis of the previous finding that the assembly of the amyloid-β protein (Aβ) into fibrils in the brain, an early and invariable pathological feature of AD, depends on the lipid environment, we determined the levels of synaptic membrane lipids in aged individuals of different APOE genotypes. In the comparison between amyloid-free ε2/ε3 and ε3/ε3 brains, the presence of the ε2 allele significantly decreased the level of cholesterol. Alternatively, in the comparison among ε3/ε3 brains, the presence of AD pathology substantially decreased the levels of cholesterol. This study suggests that the ε2 allele suppresses the initiation of AD development by lowering the cholesterol levels in synaptic membranes.

APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations

“…53, 54 Interestingly, Oikawa et al demonstrated that cholesterol levels in cortical synapses were decreased in APOE2 carriers without amyloid pathology, compared to APOE3 carriers in aged non-demented individuals. 55 We have also found the reduced cortical cholesterol levels in apoE2-TR mice compared to apoE3- and apoE4-TR mice, although cholesterol levels in CSF and plasma were significantly increased in apoE2-TR mice consistent with their apoE levels. These results suggest that intracellular and extracellular cholesterol levels are oppositely regulated by apoE levels and/or isoforms; higher apoE levels associated with APOE2 in extracellular space may lead to more abundant cholesterol loading to apoE2/lipoprotein particles, resulting in less cell-associated cholesterol but more extracellular cholesterol, which might be in equilibrium with CSF cholesterol.…”

Neuronal DNA damage response‐associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer‐type pathology

“…The pathogenesis of AD is linked to cholesterol metabolism, and is associated with genetic risk factors including apolipoprotein E (ApoE) genotype and polymorphisms in HMGCR [54][55][56][57]. However, no association between ApoE genotype and 24(S)-OHC was detected in this study, although it should be noted that the sample size for the CSF study was small.…”

Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma

“…In the CNS (both brain and CSF), however, a reversal of this imbalance was observed by this study. Although this finding was also reported in previous work (27), it is in stark contrast to another study that reported a reduced apoE4 mole fraction in the CNS comparable with the imbalance observed in the periphery (51). Together, these observations suggest different mechanisms of clearance for apoE-containing particles in the CNS than the periphery.…”