We and others have recently demonstrated that cognitive and physical stimulation in form of environmental enrichment reduces cerebral beta-amyloid (Abeta) deposition in transgenic mouse models of Alzheimer's disease. This effect was independent from amyloid precursor protein (APP) expression or processing and rather a consequence of enhanced clearance of Abeta. However, the detailed mechanisms remain unclear. In the present study, we show that environmental enrichment in TgCRND8 mice (carrying human APP(Swedish+Indiana)) affect the neurovascular unit by increased angiogenesis and differential regulation of Abeta receptor/transporter molecules, namely up-regulation of LRP1, ApoE and A2M as well as down-regulation of RAGE so that brain to blood Abeta clearance is facilitated. These results suggest a hitherto unknown effect of environmental enrichment counteracting the vascular dysfunction in Alzheimer diseased brain.