Dynamic Analysis of Amyloid β-Protein in Behaving Mice Reveals Opposing Changes in ISF versus Parenchymal Aβ during Age-Related Plaque Formation

被引:91
作者
Hong, Soyon [2 ]
Quintero-Monzon, Omar [2 ]
Ostaszewski, Beth L. [2 ]
Podlisny, Daniel R. [2 ]
Cavanaugh, William T. [2 ]
Yang, Ting [2 ]
Holtzman, David M. [3 ]
Cirrito, John R. [3 ]
Selkoe, Dennis J. [1 ,2 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Sch Med, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA 02115 USA
[3] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, Hope Ctr Neurol Disorders,Dept Neurol, St Louis, MO 63110 USA
关键词
NORMAL-PRESSURE HYDROCEPHALUS; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; IN-VIVO; SENILE PLAQUES; SHUNT RESPONSE; BRAIN; MICRODIALYSIS; A-BETA-42(43);
D O I
10.1523/JNEUROSCI.3272-11.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Growing evidence supports the hypothesis that soluble, diffusible forms of the amyloid beta-peptide (A beta) are pathogenically important in Alzheimer's disease (AD) and thus have both diagnostic and therapeutic salience. To learn more about the dynamics of soluble A beta economy in vivo, we used microdialysis to sample the brain interstitial fluid (ISF), which contains the most soluble A beta species in brain at steady state, in >40 wake, behaving APP transgenic mice before and during the process of A beta plaque formation (age 3-28 months). Diffusible forms of A beta, especially A beta(42), declined significantly in ISF as mice underwent progressive parenchymal deposition of A beta. Moreover, radiolabeled A beta administered at physiological concentrations into ISF revealed a striking difference in the fate of soluble A beta in plaque-rich (vs plaque-free) mice: it clears more rapidly from the ISF and becomes more associated with the TBS-extractable pool, suggesting that cerebral amyloid deposits can rapidly sequester soluble A beta from the ISF. Likewise, acute gamma-secretase inhibition in plaque-free mice showed a marked decline of A beta(38), A beta(40), and A beta(42), whereas in plaque-rich mice, A beta(42) declined significantly less. These results suggest that most of the A beta(42) that populates the ISF in plaque-rich mice is derived not from new A beta biosynthesis but rather from the large reservoir of less soluble A beta(42) in brain parenchyma. Together, these and other findings herein illuminate the in vivo dynamics of soluble A beta during the development of AD-type neuropathology and after gamma-secretase inhibition and help explain the apparent paradox that CSF A beta(42) levels fall as humans develop AD.
引用
收藏
页码:15861 / 15869
页数:9
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