Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Aß in human AßPP transgenic mice

Cerebral amyloid angiopathy (CAA) is a prominent pathological feature of Alzheimerʹs disease and related familial CAA disorders. However, the mechanisms that account for the cerebral vascular accumulation of amyloid ß-peptide (Aß) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human Aß precursor (AßPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular Aß. Deficient clearance of Dutch/Iowa mutant Aß 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 Aß mutations. Tg-Sw and Tg-SwDI mice expressed comparable levels of human AßPP in brain and not in peripheral tissues. However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant Aß in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type Aß. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant Aß in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type Aß in plasma. Together, these findings suggest that while wild-type Aß is readily transported out of brain into plasma, Dutch/Iowa mutant Aß is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.