| 1. |
- Martinez-Morillo, Eduardo, et al.
(författare)
-
Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls
- 2014
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 127:5, s. 633-643
-
Tidskriftsartikel (refereegranskat)abstract
- The apolipoprotein E (ApoE) epsilon 4 allele is the strongest risk factor of sporadic Alzheimer's disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE epsilon 2, epsilon 3, epsilon 4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE epsilon 4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and A beta 1-42 of which the latter association was weaker and only present in APOE epsilon 4 carriers indicating a differential involvement of ApoE in tau versus A beta-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE E > 4 carriers and whether this decrease in plasma ApoE predisposes APOE E > 4 carriers to AD.
|
|
| 2. |
- Twohig, Daniel, 1976-, et al.
(författare)
-
Molecular interactions between α-synuclein and apolipoprotein E isoforms
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for both Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Recent studies have shown that apoE4 promotes α-synuclein[J1] [DT2] pathology and that α-synuclein can be found in apoE-containing lipoprotein particles in human cerebrospinal fluid (CSF). To elucidate potential interactions between apoE isoforms and α-synuclein, we examined molecular interaction with microscale thermophoresis (MST), and assessed whether uptake of α-synuclein by cultured Lund human mesencephalic (LUHMES) neuronal progenitor cells can be modulated by apoE. We found that the dissociation constants (Kd) for apoE isoform interactions with α-synuclein ranged between 1.8 – 4.2 μM and did not differ between the apoE isoforms. Co-incubation of α-synuclein and recombinant apoE isoforms resulted in the generation of a pool of high molecular weight α-synuclein species and a reduction in α-synuclein monomers and dimers with apoE2 significantly reduced the amounts of a specific 55-kDa α-synuclein band. In turn, α-synuclein increased the levels of multimeric and high molecular weight apoE2 species, but decreased levels of apoE3 (but not apoE4) multimers by effectively stabilizing the apoE3 monomer pool in an opposite manner. Further, recombinant apoE isoforms reduced α-synuclein cellular uptake to a similar extent by approximately 20% whereas astrocyte-secreted apoE reduced cellular uptake in an apoE isoform-dependent manner (apoE2 ≤ apoE3 < apoE4). Our results demonstrate molecular interactions between apoE and α-synuclein that may result in altered cellular uptake of the latter, proposing apoE as a modulator of the extracellular pool of α-synuclein.
|
|
