Molecular interactions between α-synuclein and apolipoprotein E isoforms

• 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. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

apolipoprotein E

α-synuclein

APOE ε4

neurodegeneration

cellular uptake

neurokemi med molekylär neurobiologi

Neurochemistry with Molecular Neurobiology

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)