In humans the APOE gene is polymorphic and gives rise to three isoforms of the apolipoprotein E; E2, E3 and E4. The allele encoding the latter is the strongest known genetic risk factor for neurodegenerative disorders like Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying the increased risk of disease in APOEε4 carriers are not fully understood however we and other have reproted that apoE affects cellular uptake of the AD-related amyloid-beta peptide. Our recent results further suggest that specifically apoE4 also affects cellular uptake of alpha-synuclein, a key player in synucleinopaties like DLB. Whether alterations in protein concentrations of the apoE isoforms per se relate to disease is still under debate. We recently showed that APOEε4 carriers are deficient in plasma apoE, a deficiency attributed to a specific reduction of the apoE4 isoform only as assessed in APOE heterozygotes. Our ongoing studies further suggest that the relative ratio between plasma apoE4 and apoE3 in longitidinally followed cognitively healthy APOEε3/4 carriers is associated with brain gray matter volume  atrophy and glucose hypometabolism. We hypothesize that peripheral rather than central apoE is a risk determinant for neurodegenerative disease. We aim to assess the production and metabolism of apoE in cells representative of the systemic and central compartments. We also aim to investigate whether apoE4 fragments (rather than the intact protein) previously shown to be neurotoxic in vitro can cross the BBB and contribute to pathology.


Henrietta M Nielsen, PhD
Biträdande lektor i Neurokemi och molekylär neurobiologi
Stockholms universitet
Institutionen för neurokemi