Premium
Altering Agrin Expression Influences Aβ Deposition in APP(Swe)/PS1(ex9) Transgenic Mice
Author(s) -
Donahue John Edward,
Stopa Edward G.,
Johanson Conrad E.,
Chaudhry Hira,
Miller Miles C.,
Fallon Justin R.,
Ruegg Markus,
Rauch Steven M.,
Burgess Robert W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.707.5
Subject(s) - agrin , perlecan , chemistry , microbiology and biotechnology , gene isoform , genetically modified mouse , endocrinology , medicine , transgene , biology , proteoglycan , biochemistry , extracellular matrix , receptor , postsynaptic potential , gene
The heparan sulfate proteoglycan agrin binds to amyloid‐β (Aβ) found in senile plaques and cerebral vessels in Alzheimer disease. Aβ has also been shown to directly interact with heparan sulfate, which may affect Aβ fibril formation, proteolysis, and clearance. In the brain, neurons express agrin, suggesting that neuronal agrin can influence Aβ. Agrin is also present in the basement membrane of blood‐brain‐barrier (BBB) capillaries. Thus, BBB dysfunction may influence brain Aβ levels. We have tested the in vivo significance of agrin's interaction with Aβ using Tg mice that over‐ and underexpress agrin, combined with APP/PS1 Tg mice that form Aβ plaques. Increasing expression of both agrin isoforms caused a reduction of insoluble Aβ in the brain by ELISA and filter‐trap assays. Altering neuronal agrin did not change Aβ levels. However, the deletion of vascular agrin using an agrin conditional allele and cre expressed by the Tie2 promoter caused an increase in insoluble Aβ. Immunostaining showed reduced agrin in vessels and increased agrin in A plaques. Thus, vascular agrin loss exerts the greatest influence on Aβ deposition, and that BBB compromise may contribute to AD pathology. (Alz Assoc)