Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice.
Cerebral amyloid angiopathy (CAA) is a prominent pathological feature of Alzheimer's disease and related familial CAA disorders. However, the mechanisms that account for the cerebral vascular accumulation of amyloid beta-peptide (A beta) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human A beta precursor (A betaPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular A beta. Deficient clearance of Dutch/Iowa mutant A beta from brain across the capillary blood-brain barrier into the circulation may contribute to its potent cerebral accumulation. To further evaluate this theory, we generated a new transgenic mouse (Tg-Sw) that is nearly identical to Tg-SwDI, except lacking the Dutch/Iowa A beta mutations. Tg-Sw and Tg-SwDI mice expressed comparable levels of human A betaPP in brain and not in peripheral tissues. However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant A beta in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type A beta. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant A beta in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type A beta in plasma. Together, these findings suggest that while wild-type A beta is readily transported out of brain into plasma, Dutch/Iowa mutant A beta is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.
Davis
Judianne
J
Department of Medicine, Health Sciences Center, Stony Brook University, HSC T-15/083, Stony Brook, NY 11794-8153, USA.
Xu
Feng
F
Miao
Jianting
J
Previti
Mary Lou
ML
Romanov
Galina
G
Ziegler
Kelly
K
Van Nostrand
William E
WE
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor