title: Fyn knock-down increases Aβ, decreases phospho-tau, and worsens spatial learning in 3×Tg-AD mice.
abstract: Fyn kinase phosphorylates tau and exacerbates amyloid beta (Aβ)-mediated synaptic dysfunction. However, Fyn also increases the nonpathological cleavage of amyloid precursor protein (APP), suggesting opposing roles for Fyn in the pathogenesis of Alzheimer's disease (AD). To determine the effect of Fyn on both Aβ and tau pathologies, we crossed homozygous Alzheimer's disease triple transgenic (3×Tg) mice harboring mutations in amyloid precursor protein, presenilin-1, and tau with wild-type or Fyn knockout mice to generate Fyn(+/+)3×Tg(+/-) or Fyn(+/-)3×Tg(+/-) mice. We found that Fyn(+/-)3×Tg(+/-) mice had increased soluble and intracellular Aβ, and these changes were accompanied by impaired performance on the Morris water maze at 18 months. Fyn(+/-)3×Tg(+/-) mice had decreased phosphorylated tau at 15-18 months (as did Fyn knockout mice), but Fyn(+/-)3×Tg(+/-) mice had increased phosphorylated tau by 24 months. In addition, we observed that Fyn(+/-)3×Tg(+/-) males were delayed in developing Aβ pathology compared with females, and displayed better spatial learning performance at 18 months. Overall, these findings suggest that loss of Fyn at early stages of disease increases soluble Aβ accumulation and worsens spatial learning in the absence of changes in tau phosphorylation.
authors: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057-1464, USA.
authors: S Sakura
authors: SS
authors: Minami
authors: Thomas G
authors: TG
authors: Clifford
authors: Hyang-Sook
authors: HS
authors: Hoe
authors: Yasuji
authors: Y
authors: Matsuoka
authors: G William
authors: GW
authors: Rebeck
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency*; D012737:Sex Factors; D013028:Space Perception / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn