Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.
Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta (Abeta) 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 Abeta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of Abeta 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 higher Abeta 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 Abeta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate Abeta levels, and inhibition of Fyn activity may help counteract Abeta-induced impairments.
Chin
Jeannie
J
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Palop
Jorge J
JJ
Puoliväli
Jukka
J
Massaro
Catherine
C
Bien-Ly
Nga
N
Gerstein
Hilary
H
Scearce-Levie
Kimberly
K
Masliah
Eliezer
E
Mucke
Lennart
L
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000818:Animals; D003072:Cognition Disorders / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051076:Proto-Oncogene Proteins c-fyn / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013569:Synapses / Q000201:enzymology* / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn