Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy.
OBJECTIVE
Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established.


METHODS
We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window.


RESULTS
Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 24 months, all cerebrovascular responses were markedly reduced. At this time, there was evidence of cerebrovascular amyloid deposition, smooth muscle fragmentation, and pericyte loss. Neocortical superfusion with the free radical scavenger manganic(I-II)meso-tetrakis(4-benzoic acid) porphyrin rescued endothelium-dependent responses and functional hyperemia completely at 3 months but only partially at 18 months.


CONCLUSIONS
Tg-SwDI mice exhibit a profound age-dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms. Early in the disease process, oxidative stress is responsible for most of the vascular dysfunction, but with advancing disease structural alterations of the vasomotor apparatus also play a role. Early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy.
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
Laibaik
L
Park
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
Kenzo
K
Koizumi
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
Sleiman
S
El Jamal
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
Ping
P
Zhou
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
Mary Lou
ML
Previti
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
William E
WE
Van Nostrand
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.).
George
G
Carlson
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (L.P., K.K., S.E.J., P.Z., C.I.); Department of Neurosurgery, Stony Brook University, NY (M.L.P., W.E.V.N.); and McLaughlin Research Institute, Great Falls, MT (G.C.). coi2001@med.cornell.edu.
Costantino
C
Iadecola
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001783:Blood Flow Velocity; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013003:Somatosensory Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D016229:Amyloid beta-Peptides
amyloid-β; cerebral blood flow; cerebrovascular disorder