Chloroquine administration in mice increases beta-amyloid immunoreactivity and attenuates kainate-induced blood-brain barrier dysfunction.
The anti-malarial drug chloroquine (CHL) has been reported to cause the accumulation of beta-amyloid peptide containing fragments (fA beta) of the amyloid precursor protein within lysosomes in vitro. However, the significance of this finding with regards to the development of Alzheimer's disease (AD) pathology in vivo is not known. Hence, we investigated the effects of chronic CHL administration in the mouse. Systemically administered CHL caused an astrocytic response and an increase in intracellular A beta immunoreactivity throughout the brain, but no plaque-like pathology. Pharmacological challenge with the excitotoxin kainic acid (KA) revealed a mild proconvulsant effect of CHL pretreatment (P < 0.06). Interestingly, CHL protected the blood-brain barrier from characteristic KA-induced dysfunction. Given the hypothesized involvement of both excitotoxic processes and the vascular system in AD, the observed interactions may assist in elucidating the pathogenesis of AD.
Mielke
J G
JG
Department of Psychology, University of Toronto, Scarborough, ONT, Canada.
Murphy
M P
MP
Maritz
J
J
Bengualid
K M
KM
Ivy
G O
GO
D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D000962:Antimalarials / Q000494:pharmacology*; D001253:Astrocytes / Q000737:chemistry / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002738:Chloroquine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism* / Q000494:pharmacology; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D000962:Antimalarials; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D002738:Chloroquine; D007608:Kainic Acid