期刊
BRAIN RESEARCH
卷 1142, 期 -, 页码 223-236出版社
ELSEVIER
DOI: 10.1016/j.brainres.2007.01.070
关键词
Alzheimer's disease; amyloid; blood-brain barrier; pertussis toxin; A beta 42; neuron
资金
- NIA NIH HHS [AG00925] Funding Source: Medline
We have investigated the possibility that soluble, blood-borne amyloid beta (A beta) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. immunohistochemical analyses revealed extravasated plasma components, including A beta 42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne A beta peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled A beta 42 and A beta 40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both A beta 40 and A beta 42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, A beta 42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, A beta 42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous A beta 42. An intact BBB (saline-injected controls) blocked entry of blood-borne A beta peptides into the brain. The neuronal subtype selectivity of A beta 42 and A beta 40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. A beta 40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas A beta 42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous A beta peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells. (c) 2007 Elsevier B.V. All rights reserved.
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