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.
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.
Keene
C Dirk
CD
Harborview Medical Center, Box 359645, 325 Ninth Ave, Seattle, WA 98104, USA. cdkeene@u.washington.edu
Chang
Rubens C
RC
Lopez-Yglesias
Americo H
AH
Shalloway
Bryan R
BR
Sokal
Izabella
I
Li
Xianwu
X
Reed
Patrick J
PJ
Keene
Lisa M
LM
Montine
Kathleen S
KS
Breyer
Richard M
RM
Rockhill
Jason K
JK
Montine
Thomas J
TJ
D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D058307:Receptors, Prostaglandin E, EP2 Subtype