Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology.
Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allogeneic bone marrow cells. Here, we report a marked reduction in amyloid-β (Aβ) levels, β-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.
Zhu
Yuyan
Y
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL 33613, USA.
Obregon
Demian
D
Hou
Huayan
H
Giunta
Brian
B
Ehrhart
Jared
J
Fernandez
Frank
F
Mori
Takashi
T
Nikolic
William
W
Zhao
Yangbing
Y
Morgan
Dave
D
Town
Terrence
T
Tan
Jun
J
D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D058225:Plaque, Amyloid; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; D016207:Cytokines; D050505:Mutant Proteins; D053764:Presenilin-1