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The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.

ABSTRACT: The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients' brain. We have previously shown that a specific apoE4 fragment, apoE4-165, promotes amyloid-peptide beta 42 (A?42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events considered to occur early in AD pathogenesis. Here, we show that these effects are allele-dependent and absolutely require the apoE4 background. Furthermore, the exact length of the fragment is critical since longer or shorter length carboxyl-terminal truncated apoE4 forms do not elicit the same effects. Structural and thermodynamic analyses showed that apoE4-165 has a compact structure, in contrast to other carboxyl-terminal truncated apoE4 forms that are instead destabilized. Compared however to other allelic backgrounds, apoE4-165 is structurally distinct and less thermodynamically stable suggesting that the combination of a well-folded structure with structural plasticity is a unique characteristic of this fragment. Overall, our findings suggest that the ability of apoE fragments to promote A?42 intraneuronal accumulation is specific for both the apoE4 isoform and the particular structural and thermodynamic properties of the fragment.

SUBMITTER: Dafnis I

PROVIDER: S-EPMC4967930 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.

Dafnis Ioannis I Argyri Letta L Sagnou Marina M Tzinia Athina A Tsilibary Effie C EC Stratikos Efstratios E Chroni Angeliki A

Scientific reports 20160801

The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients' brain. We have previously shown that a specific apoE4 fragment, apoE4-165, promotes amyloid-peptide beta 42 (Aβ42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events consider ...[more]

PMID: 27476701

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Project description:Accumulation of amyloid-? peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-? species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-? and full-length amyloid-?, depending on disease stage as well as brain area, and determined how these amyloid-? species respectively correlate with clinicopathological features of Alzheimer's disease. To this end, the amounts of amyloid-? species and other proteins related to amyloid-? metabolism or Alzheimer's disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer's disease cases (n = 19), neurologically normal elderly without amyloid-? accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-? accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-?42 and full-length amyloid-?42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-?40 and full-length amyloid-?40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-?42 accumulation was increased in Alzheimer's disease compared to pathological ageing, whereas cortical full-length amyloid-?42 accumulation was comparable between Alzheimer's disease and pathological ageing. Moreover, N-terminally truncated amyloid-?42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-?42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-?42 species, represented by pyroglutamylated amyloid-?11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-?42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-?42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-?42 accumulation than those of other amyloid-? species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-?11-x fibrils than full-length amyloid-? fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-?42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-?42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-?42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-? species could play critical roles in the disease by linking other clinicopathological features of Alzheimer's disease.

Dataset Information

The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.

Publications

The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.

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