Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes

Abstract

BackgroundIt is suspected that excess of brain cholesterol plays a role in Alzheimer’s disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.ResultsWe thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.ConclusionsMembrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-60) contains supplementary material, which is available to authorized users.

APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations

“…49, 52 In addition, increases in cholesterol in neurons also promote amyloid-β accumulation and AD-related abnormal pathologies. 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.…”

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

“…Another study also suggested that APOE4 might accelerate endocytosis into the endosome (Ye et al, 2005). Since APOE4 exemplifies the class of cholesterol metabolism genes, it is noteworthy that altering the cholesterol levels of neurons (Marquer et al, 2014), or cholesterol transport within neurons (Jin et al, 2004), induces enlarged endosomes, reflective of putative endosomal traffic jams.…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…More complex models may be required to improve the translational potential of APOE research. In this regard, results from in vivo animal studies would be complemented with recent advances in in vitro experimental technologies [204], including induced pluripotent stem cell (iPSC)-based models [205, 206] and three-dimensional culture systems [207], recapitulating true human brain biology in a dish. In addition, the translational potential of AD therapeutics targeting apoE may be enhanced via more careful preclinical study design in animal models such as the utilization of heterogeneous animal cohorts with variations in age, sex, strain and comorbidities such as hyperglycemia, hypertension and chronic cerebral hypo-perfusion.…”