Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model.
OBJECTIVE
To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood-brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10-12 months of age.


METHODS
We assessed BBB integrity using well-established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate.


RESULTS
BBB permeability is increased in the cerebral cortex of 10-month-old Tg2576 mice preceding Alzheimer disease pathology presentation. Furthermore, when compared with their nontransgenic littermates, 4-month-old Tg2576 mice exhibit compromised BBB integrity in some areas of the cerebral cortex. An age-related increase in albumin uptake by the brains of Tg2576 mice, compared with nontransgenic mice, was also observed. These findings were supported by quantitative Evans blue analysis (p = 0.07, two-way analysis of variance).


CONCLUSIONS
A breakdown of BBB was evident in young 4- to 10-month-old Tg2576 mice. Compromised barrier function could explain the mechanisms of Abeta entry into the brain observed in experimental Alzheimer disease vaccination models. Such structural changes to the BBB caused by elevated Abeta could play a central role in Alzheimer disease development and might define an early point of intervention for designing effective therapy against the disease.
Ujiie
Maki
M
Biotechnology Laboratory, University of British Columbia, Vancouver V6T 1Z3, Canada.
Dickstein
Dara L
DL
Carlow
Douglas A
DA
Jefferies
Wilfred A
WA
D000375:Aging / Q000378:metabolism; D000418:Albumins / Q000493:pharmacokinetics; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier; D002199:Capillary Permeability; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005070:Evans Blue / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D058225:Plaque, Amyloid / Q000473:pathology*; D013997:Time Factors
D000418:Albumins; D005070:Evans Blue