Targeting apolipoprotein E and N-terminal amyloid β-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice

Darrell Sawmiller; Naoki Koyama; Masakazu Fujiwara; Tatsuya Segawa; Masahiro Maeda; Takashi Mori

doi:10.1016/j.jbc.2023.104846

Targeting apolipoprotein E and N-terminal amyloid β-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice

J Biol Chem. 2023 Jul;299(7):104846. doi: 10.1016/j.jbc.2023.104846. Epub 2023 May 19.

Authors

Darrell Sawmiller¹, Naoki Koyama², Masakazu Fujiwara², Tatsuya Segawa³, Masahiro Maeda³, Takashi Mori⁴

Affiliations

¹ Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA. Electronic address: dsawmill@usf.edu.
² Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan.
³ Immuno-Biological Laboratories Co, Ltd, Fujioka, Gunma, Japan.
⁴ Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan; Department of Pathology, Saitama Medical Center and University, Kawagoe, Saitama, Japan. Electronic address: t_mori@saitama-med.ac.jp.

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.

Keywords: Alzheimer’s disease; amyloid β-protein; amyloid β-protein precursor; apolipoprotein E; isoform; low-density lipoprotein receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor* / metabolism
Animals
Apolipoproteins E / antagonists & inhibitors
Apolipoproteins E / genetics
Cognition / drug effects
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Apolipoproteins E
Neuroprotective Agents