Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons

Deposition of amyloid beta-peptide (A beta) in cerebral vessel walls (cereb ral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and oc curs also as a sporadic disorder, Here, we describe significant CAA in addi tion to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neur ons. The number of amyloid-bearing vessels increased with age, from similar to 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles a nd ranged from small focal to large circumferential depositions. Ultrastruc tural analysis allowed us to identify specific features contributing to wea kening of the vessel mall and aneurism formation, ie, disruption of the ext ernal elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically , the much lower A beta 42:A beta 40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls A beta 40 was the m ore abundant amyloid peptide. The exclusive neuronal origin of transgenic A PP, the high levels of A beta in cerebrospinal fluid compared to plasma, an d the specific neuroanatomical localization of vascular amyloid strongly su ggest specific drainage pathways, rather than local production or blood upt ake of A beta as the primary mechanism underlying CAA, The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for A beta 42, suggests that, similar to senile plaque formation, A beta 42 may be the first amyloid to be deposited in the vessel walls and that it entra ps the more soluble A beta 40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of A beta 40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively highe r levels of A beta 42, caused an increase in CAA and senile plaques. This m ouse model will be useful in further elucidating the pathogenesis of CAA an d Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.