Reducing cerebral microvascular amyloid-beta protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic mice.
Cerebral microvascular amyloid-beta (Abeta) protein deposition is emerging as an important contributory factor to neuroinflammation and dementia in Alzheimer's disease and related familial cerebral amyloid angiopathy disorders. In particular, cerebral microvascular amyloid deposition, but not parenchymal amyloid, is more often correlated with dementia. Recently, we generated transgenic mice (Tg-SwDI) expressing the vasculotropic Dutch (E693Q)/Iowa (D694N) mutant human Abeta precursor protein in brain that accumulate abundant cerebral microvascular fibrillar amyloid deposits. In the present study, our aim was to assess how the presence or absence of fibrillar Abeta deposition in the cerebral microvasculature affects neuroinflammation in Tg-SwDI mice. Using Tg-SwDI mice bred onto an apolipoprotein E gene knock-out background, we found a strong reduction of fibrillar cerebral microvascular Abeta deposition, which was accompanied by a sharp decrease in microvascular-associated neuroinflammatory cells and interleukin-1beta levels. Quantitative immunochemical measurements showed that this reduction of the neuroinflammation occurred in the absence of lowering the levels of total Abeta40/Abeta42 or soluble Abeta oligomers in brain. These findings suggest that specifically reducing cerebral microvascular fibrillar Abeta deposition, in the absence of lowering either the total amount of Abeta or soluble Abeta oligomers in brain, may be sufficient to ameliorate microvascular amyloid-associated neuroinflammation.
Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153, USA.
Jianting
J
Miao
Michael P
MP
Vitek
Feng
F
Xu
Mary Lou
ML
Previti
Judianne
J
Davis
William E
WE
Van Nostrand
D000544:Alzheimer Disease / Q000473:pathology; D028227:Amyloid Neuropathies, Familial / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001253:Astrocytes / Q000473:pathology; D001812:Blood-Brain Barrier; D002196:Capillaries / Q000737:chemistry* / Q000473:pathology; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics / Q000473:pathology*; D002560:Cerebrovascular Circulation; D003433:Crosses, Genetic; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation; D017628:Microglia / Q000473:pathology
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D007375:Interleukin-1