title: Submyeloablative conditioning with busulfan permits bone marrow-derived cell accumulation in a murine model of Alzheimer's disease.
abstract: Previous work has suggested that bone marrow (BM)-derived cells (BMDCs) accumulate within the CNS and could potentially associate with β-amyloid plaques in Alzheimer's disease (AD). To explore the accumulation of BMDCs in murine AD, we transplanted green fluorescent protein (GFP)-labeled BM cells into triple transgenic (3×Tg) and wild-type (wt) mice using non-irradiative myelosuppresive conditioning with busulfan (BU). We find that BU (80mg/kg) is sufficient to obtain adequate chimerism (>85%) in wt mice. In order to obtain appreciable non-irradiative chimerism in the 3×Tg mice (>80%), anti-asialo ganglio-N-tetraosylceramide (α-ASGM-1) antibody was also used to reduce natural killer cell function and thereby abrogate the hybrid resistance of the 3×Tg mouse strain. Using BU conditioning and α-ASGM-1 together, we observed sustained BM chimerism and BMDC accumulation within the CNS of the 3×Tg and wt mice. In cortex and hippocampus, BMDC accumulation was perivascular in distribution and similar between 3×Tg and wt mice, with no clear association between BMDCs and AD plaques. We conclude that non-irradiative BM chimerism can be achieved with BU in 3×Tg mice, but requires α-ASGM-1 (or similar appropriate NK-cell depletion). Use of this chimerism protocol permits BMDCs accumulation in the CNS of mixed strain recipient mice although BMDCs appear to be largely perivascular within cortex and hippocampus.
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Dr., Burnaby, BC V5A 1S6, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Barr
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Dr., Burnaby, BC V5A 1S6, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Manning
authors.affiliation: Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Coral Ann B
authors.initials: CA
authors.lastname: Lewis
authors.affiliation: Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Fabio M V
authors.initials: FM
authors.lastname: Rossi
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Dr., Burnaby, BC V5A 1S6, Canada. Electronic address: ckrieger@sfu.ca.
authors.forename: Charles
authors.initials: C
authors.lastname: Krieger
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D016026:Bone Marrow Transplantation; D001921:Brain / Q000473:pathology; D002066:Busulfan / Q000494:pharmacology*; D008822:Mice, Transgenic; D013116:Spinal Cord / Q000473:pathology; D018183:Transplantation Chimera; D019172:Transplantation Conditioning
chemical_list: D002066:Busulfan
keywords: 3×Tg mice; Bone marrow-derived cells; Busulfan; Busulfex; Chimerism; Hybrid resistance