Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer's disease mutations.
Mutations in the presenilin 1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). Besides senile plaques, neurofibrillary tangles, and neuronal loss, Alzheimer's disease (AD) is also accompanied by vascular pathology. Here we describe an age-related vascular pathology in two lines of PS1 FAD-mutant transgenic mice that mimics many features of the vascular pathology seen in AD. The pathology was especially prominent in the microvasculature whose vessels became thinned and irregular with the appearance of many abnormally looped vessels as well as string vessels. Stereologic assessments revealed a reduction of the microvasculature in the hippocampus that was accompanied by hippocampal atrophy. The vascular changes were not congophilic. Yet, despite the lack of congophilia, penetrating vessels at the cortical surface were often abnormal morphologically and microhemorrhages sometimes occurred. Altered immunostaining of blood vessels with basement membrane-associated antigens was an early feature of the microangiopathy and was associated with thickening of the vascular basal laminae and endothelial cell alterations that were visible ultrastructurally. Interestingly, although the FAD-mutant transgene was expressed in neurons in both lines of mice, there was no detectable expression in vascular endothelial cells or glial cells. These studies thus have implications for the role of neuronal to vascular signaling in the pathogenesis of the vascular pathology associated with AD.
Gama Sosa
Miguel A
MA
Research and Development, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA.
Gasperi
Rita De
RD
Rocher
Anne B
AB
Wang
Athena Ching-Jung
AC
Janssen
William G M
WG
Flores
Tony
T
Perez
Gissel M
GM
Schmeidler
James
J
Dickstein
Dara L
DL
Hof
Patrick R
PR
Elder
Gregory A
GA
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001284:Atrophy; D001485:Basement Membrane / Q000378:metabolism; D001808:Blood Vessels / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D027042:Chromosomes, Artificial, P1 Bacteriophage / Q000235:genetics; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1 / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D016326:Extracellular Matrix Proteins; D050505:Mutant Proteins; D053764:Presenilin-1