Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons

Abstract

Human apolipoprotein (apo) E4, a major risk factor for Alzheimer's disease (AD), occurs in amyloid plaques and neurofibrillary tangles (NFTs) in AD brains; however, its role in the pathogenesis of these lesions is unclear. Here we demonstrate that carboxyl-terminaltruncated forms of apoE, which occur in AD brains and cultured neurons, induce intracellular NFT-like inclusions in neurons. These cytosolic inclusions were composed of phosphorylated tau, phosphorylated neurofilaments of high molecular weight, and truncated apoE. Truncated apoE4, especially apoE4(⌬272-299), induced inclusions in up to 75% of transfected neuronal cells, but not in transfected nonneuronal cells. ApoE4 was more susceptible to truncation than apoE3 and resulted in much greater intracellular inclusion formation. These results suggest that apoE4 preferentially undergoes intracellular processing, creating a bioactive fragment that interacts with cytoskeletal components and induces NFT-like inclusions containing phosphorylated tau and phosphorylated neurofilaments of high molecular weight in neurons.

Impairments in spatial memory retention of GFAP-apoE4 female mice

“…when apoE was expressed in neurons in culture or in neurons in transgenic mice but not when it was expressed in non-neuronal cells in culture or non-neuronal cells in transgenic mice [10]. Consistent with these data, a role for astrocytic apoE has been suggested in mitochondrial dysfunction and neurofibrillary tangle formation, while a role for neuronal apoE has been suggested in amyloid plaque formation [22].…”

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

“…10 There is significant evidence that degradation fragments of the apoE4 protein have a greater neurotoxic effect on mitochondrial function over time compared to apoE3 or apoE2 fragments. [28][29][30][31] These fragments, found in cultured neuronal cells and AD brain, induce neurofibrillary tangle-like structures and cause neurotoxicity in vitro. 28,31 When expressed in transgenic mice, the fragments cause neurodegeneration and behavioral deficits.…”

“…[28][29][30][31] These fragments, found in cultured neuronal cells and AD brain, induce neurofibrillary tangle-like structures and cause neurotoxicity in vitro. 28,31 When expressed in transgenic mice, the fragments cause neurodegeneration and behavioral deficits. 30 One hypothesis is that apoE fragments escape from the secretory pathway and enter the cytoplasm, where the lipid-binding region of the fragment mediates interactions with the mitochondria.…”

“…30 One hypothesis is that apoE fragments escape from the secretory pathway and enter the cytoplasm, where the lipid-binding region of the fragment mediates interactions with the mitochondria. 28 ApoE4 is more susceptible to degradation owing to protein folding differences between the isoforms. 18,30,31 At a mechanistic level, the relationship between APOE, RSG and cognition has not been elucidated.…”

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

“…The carboxyl-truncated apoE fragment (~29 kDa) was seen only in the corneas of apoE4 mice ( Figure 7B). To verify that the ~29 kDa band was the C-terminal truncated apoE fragment of human apoE, we used a separate polyclonal antibody (generously provided by Dr. Y Huang, Gladstone Institute of Cardiovascular Diseases, San Francisco, CA) against apoE C-terminal amino acids 272--299 and analyzed the pattern of apoE4 corneal homogenates using Western blot analysis (Huang et al, 2001). The antibody against C-terminal amino acids 272--299 failed to detect the ~29 kDa apoE protein fragment in HSV-1 infected apoE4 corneas, but recognized the full-length (34 kDa) apoE ( Figure 7C).…”