ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo.
Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins. apoE(-/-) and clusterin(-/-) mice accumulated similar Abeta levels but much less fibrillar Abeta. In contrast, apoE(-/-)/clusterin(-/-) mice had both earlier onset and markedly increased Abeta and amyloid deposition. Both apoE(-/-) and apoE(-/-)/clusterin(-/-) mice had elevated CSF and brain interstitial fluid Abeta, as well as significant differences in the elimination half-life of interstitial fluid Abeta measured by in vivo microdialysis. These findings demonstrate additive effects of apoE and clusterin on influencing Abeta deposition and that apoE plays an important role in regulating extracellular CNS Abeta metabolism independent of Abeta synthesis.
DeMattos
Ronald B
RB
Neuroscience Discovery Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. holtzman@neuro.wustl.edu
Cirrito
John R
JR
Parsadanian
Maia
M
May
Patrick C
PC
O'Dell
Mark A
MA
Taylor
Jennie W
JW
Harmony
Judith A K
JA
Aronow
Bruce J
BJ
Bales
Kelly R
KR
Paul
Steven M
SM
Holtzman
David M
DM
D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D051152:Clusterin; D005110:Extracellular Space / Q000378:metabolism; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006207:Half-Life; D006651:Histocytochemistry; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones