Suppressed Accumulation of Cerebral Amyloid {beta} Peptides in Aged Transgenic Alzheimer's Disease Mice by Transplantation with Wild-type or Prostaglandin E2 Receptor Subtype 2-null Bone Marrow

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Jun 5

PMID 20522650

Citations 38

Authors

C Dirk Keene

Rubens C Chang

Americo H Lopez-Yglesias

Bryan R Shalloway

Izabella Sokal

Xianwu Li

Patrick J Reed

Lisa M Keene

Kathleen S Montine

Richard M Breyer

Jason K Rockhill

Thomas J Montine

Affiliations

Soon will be listed here.

Abstract

A complex therapeutic challenge for Alzheimer's disease (AD) is minimizing deleterious aspects of microglial activation while maximizing beneficial actions, including phagocytosis/clearance of amyloid beta (Abeta) peptides. One potential target is selective suppression of microglial prostaglandin E(2) receptor subtype 2 (EP2) function, which influences microglial phagocytosis and elaboration of neurotoxic cytokines. To test this hypothesis, we transplanted bone marrow cells derived from wild-type mice or mice homozygous deficient for EP2 (EP2(-/-)) into lethally irradiated 5-month-old wild-type or APPswe-PS1DeltaE9 double transgenic AD mouse model recipients. We found that cerebral engraftment by bone marrow transplant (BMT)-derived wild-type or EP2(-/-) microglia was more efficient in APPswe-PS1DeltaE9 than in wild-type mice, and APPswe-PS1DeltaE9 mice that received EP2(-/-) BMT had increased cortical microglia compared with APPswe-PS1DeltaE9 mice that received wild-type BMT. We found that myeloablative irradiation followed by bone marrow transplant-derived microglia engraftment, rather than cranial irradiation or BMT alone, was responsible for the approximate one-third reduction in both Abeta plaques and potentially more neurotoxic soluble Abeta species. An additional 25% reduction in cerebral cortical Abeta burden was achieved in mice that received EP2(-/-) BMT compared with mice that received wild-type BMT. Our results provide a foundation for an adult stem cell-based therapy to suppress soluble Abeta peptide and plaque accumulation in the cerebrum of patients with AD.

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