In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles.
The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.
Härtig
Wolfgang
W
Paul Flechsig Institute for Brain Research, Faculty of Medicine, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany. hartig@medizin.uni-leipzig.de
Kacza
Johannes
J
Paulke
Bernd-Reiner
BR
Grosche
Jens
J
Bauer
Ute
U
Hoffmann
Anke
A
Elsinghorst
Paul W
PW
Gütschow
Michael
M
D000166:Acridines / Q000008:administration & dosage / Q000378:metabolism*; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D002867:Chromones / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004659:Enbucrilate; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles; D058225:Plaque, Amyloid / Q000378:metabolism; D011109:Polymethacrylic Acids; D011137:Polystyrenes; D053764:Presenilin-1 / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
C548658:2-(4-(((7-diethylamino)-2,4-dioxo-2H-chromen-3(4H)-ylidenemethyl)amino)phenyl)-N-1,2,3,4-tetrahydroacridin-9-ylacetohydrazide; D000166:Acridines; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D002867:Chromones; D005456:Fluorescent Dyes; D011109:Polymethacrylic Acids; D011137:Polystyrenes; D053764:Presenilin-1; D016875:tau Proteins; C042535:polyglycidyl methacrylate; D004659:Enbucrilate