Brain interstitial oligomeric amyloid ? increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.

ABSTRACT: There is a growing body of evidence that soluble oligomeric forms of amyloid ? (A?) play a critical role in Alzheimer's disease (AD). Despite the importance of soluble A? oligomers as a therapeutic target for AD, the dynamic metabolism of these A? species in vivo has not been elucidated because of the difficulty in monitoring brain A? oligomers in living animals. Here, using a unique large pore-sized membrane microdialysis, we characterized soluble A? oligomers in brain interstitial fluid (ISF) of awake, freely moving APP/PS1 transgenic and control WT mice. We could detect high-molecular-weight (HMW) and low-molecular-weight (LMW) A? oligomers in the brain ISF of living animals, which increased dramatically in an age-dependent manner (5- to 8-fold increase, 4 vs. 17-18 mo). Notably, HMW A? decreased more slowly than other forms of A? after acute ?-secretase inhibition [% decrease from the baseline (HMW vs. LMW) was 36.9 vs. 74.1% (A?40, P<0.05) and 25.4 vs. 88.0% (A?42, P<0.01)], suggesting that HMW A? oligomers clear more slowly than other forms from the brain. These data reveal the dynamic metabolism of neurotoxic A? oligomers in AD brain and could provide new insights into A?-targeted therapies for AD.

SUBMITTER: Takeda S 

PROVIDER: S-EPMC3714573 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature