Editors' ChoiceAlzheimer’s Disease

Alzheimer’s medicine: β-Amyloid takes a siP

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ec200
DOI: 10.1126/scitranslmed.aal3698

The interaction of soluble β-amyloid (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), with EphB2 receptors is thought to promote depletion of EphB2 receptors from the neuronal cell membrane. Since these receptors are important in maintaining integrity of the N-methyl-D-aspartate (NMDA) receptor—itself important in synaptic plasticity—loss of EphB2 may be a mediator of Aβ-induced neuronal dysfunction. To combat this loss, Shi and colleagues used small interfering peptides (siPs) to block ADDL-EphB2 interactions, rescuing NMDA receptor integrity and memory deficits in a mouse model of Alzheimer’s disease (AD).

In cultured rat hippocampal neurons, treatment with ADDLs led to an acute reduction in EphB2 expression and surface localization of the NMDA receptor subunit GluN2B, whereas total GluN2B expression was unaltered. ADDLs interacted with EphB2 through its fibronectin type 3 repeat domain, and two siPs synthesized from the sequence of this domain bound to ADDLs in vitro to competitively inhibit EphB2 binding. One of these siPs, Pep63, prevented the loss of EphB2 and surface expression of GluN2B in hippocampal cultures. The effects of Pep63 were pursued further in vivo via bilateral injection for 5 days into the hippocampus of mice expressing both chimeric mouse/human mutated amyloid precursor protein and mutated human presenilin-1. These mice exhibit age-associated deficits in context- and tone-dependent fear memory along with behavioral impairment in spatial learning and memory that were all rescued by Pep63 treatment. Reductions in EphB2 and active GluN2B protein expression were rescued by Pep63, suggesting that functional NMDA receptors may be preserved in these mice.

Progress has been made in developing AD treatments to prevent Aβ neurotoxicity, such as β- or γ-secretase inhibitors and immunotherapy with antibodies that prevent Aβ aggregation. Blocking neurotoxic cascades initiated by Aβ, achieved through the use of siPs in this study, may offer an alternative or complementary approach that renders harmless any toxic oligomers present without depending on altering the levels of ADDLs. The efficacy of long-term treatment with peptide drugs on AD pathology and progression will be an important area of future study.

X.-D. Shi et al., locking the interaction between EphB2 and ADDLs by a small peptide rescues impaired synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease. J. Neurosci. 36 11959–11973 (2016). [Abstract]

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