AI Article Synopsis

  • ApoE's interaction with amyloid β-protein precursor (APP) is a key target for Alzheimer's disease therapy, and researchers discovered an apoE antagonist called 6KApoEp that effectively blocks this interaction.
  • Treatment of APP/PS1 mice, which represent different human apoE isoforms, with 6KApoEp improved cognitive impairment and memory performance, showing benefits across all mouse lines tested without affecting non-transgenic controls.
  • Additionally, 6KApoEp significantly reduced brain amyloid β deposits and improved APP processing, especially in mice carrying the more Alzheimer's-prone apoE4 isoform, indicating its potential as a therapeutic strategy for Alzheimer’s patients with this genetic background.

Article Abstract

Apolipoprotein E (apoE) interaction with amyloid β-protein precursor (APP) has garnered attention as the therapeutic target for Alzheimer's disease (AD). Having discovered the apoE antagonist (6KApoEp) that blocks apoE binding to N-terminal APP, we tested the therapeutic potential of 6KApoEp on AD-relevant phenotypes in amyloid β-protein precursor/presenilin 1 (APP/PS1) mice that express each human apoE isoform of apoE2, apoE3, or apoE4 (designated APP/PS1/E2, APP/PS1/E3, or APP/PS1/E4 mice). At 12 months of age, we intraperitoneally administered 6KApoEp (250 μg/kg) or vehicle once daily for 3 months. At 15 months of age, blockage of apoE and N-terminal APP interaction by 6KApoEp treatment improved cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse line and did not alter behavior in nontransgenic littermates. Moreover, 6KApoEp therapy ameliorated brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-protein (Aβ) in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse group. Notably, the highest effect in Aβ-lowering by 6KApoEp treatment was observed in APP/PS1/E4 mice versus APP/PS1/E2 or APP/PS1/E3 mice. These effects occured through shifting toward lessened amyloidogenic APP processing due to decreasing APP abundance at the plasma membrane, reducing APP transcription, and inhibiting p44/42 mitogen-activated protein kinase phosphorylation. Our findings provide the preclinical evidence that 6KApoEp therapy aimed at targeting apoE and N-terminal APP interaction is a promising strategy and may be suitable for patients with AD carrying the apoE4 isoform.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331488PMC
http://dx.doi.org/10.1016/j.jbc.2023.104846DOI Listing

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