Cytotoxic ApoE Cannot Reach Nucleus from Cytosol

Hence No Effect on Gene Expression, or Effect on Microtubules

Ronald B. DeMattos (now at Eli Lilly in Indianapolis), Fayanne E. Thorngate (still at SUNY), and David L. Williams (deceased in early 2000s?) . . . Department of Pharmacological Sciences, University Medical Center, State University of New York at Stony Brook, Stony Brook, New York 11794

Abstract: Genetic evidence indicates that apolipoprotein E4 (apoE4) is a risk factor for the development of Alzheimer’s disease. A controversial hypothesis proposes that apoE, a typical secretory protein, accesses the neuronal cytosol in which apoE3, but not apoE4, protects tau from hyperphosphorylation. However, no conclusive evidence for the presence of apoE in the cytosolic compartment has been presented. We designed a novel assay to test whether apoE can access the cytosol via escape from the endocytic pathway by incorporating a nuclear localization signal (NLS) into apoE. Control experiments demonstrated that apoE plus NLS (apoE+NLS) is chaperoned to the nucleus if it reaches the cytosolic compartment. When exogenous apoE+NLS was endocytosed by neuronal cells, no nuclear apoE was detected, indicating that apoE remains within the endocytic pathway and does not escape into the cytosol. Furthermore, we show that direct cytosolic expression of apoE is cytotoxic. These data argue that effects of apoE on the neuronal cytoskeleton and on neurite outgrowth are not mediated via cytosolic interactions but rather by actions originating at the cell surface.

DeMattos et. al. is a reaction to In vitro research about the allegedly toxic nature of apoE4 proteins.

The paper then goes on to show that ApoE proteins are confined to lisosomes, and do not normally enter neuronal cytosol (fluid and material within the cell membrane), much less the nucleus of the cell.

DeMattos describes using Neuro-2a neuroblastoma cells transfected with plasmid coding for either secreted apoE (outside the cell) or intracellular apoE (inside the cell membrane in the endosomes, cytosol, and nucleus.


The second sentence points at some papers worth reading about ApoE production outside the liver

and in the brain

where it is secreted by astrocytes and microglial cells (as naked molecules or as part of lipid packages?)

What's happened since?

36 Citations on Google Scholar, 25 available

T Hosono and M Michikawa - Molecular Neurodegeneration, 2009

Cytotoxic (last edited 2020-03-29 00:44:21 by KeithLofstrom)