Fyn kinase induces synaptic and cognitive impairments in a Transgenic mouse model of Alzheimer's disease

被引:265
作者
Chin, J
Palop, JJ
Puoliväli, J
Massaro, C
Bien-Ly, N
Gerstein, H
Scearce-Levie, K
Masliah, E
Mucke, L
机构
[1] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA
[3] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 USA
[4] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
关键词
hippocampus; plasticity; amyloid beta; Arc; spatial memory; striatal-enriched phosphatase ( STEP);
D O I
10.1523/JNEUROSCI.2980-05.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta(A beta) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates A beta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of A beta production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higherA beta levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of A beta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate A beta levels, and inhibition of Fyn activity may help counteract A beta-induced impairments.
引用
收藏
页码:9694 / 9703
页数:10
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