Focal cerebral ischemia in rats alters APP processing and expression of Abeta peptide degrading enzymes in the thalamus.
We have previously demonstrated aggregation of amyloid precursor protein (APP) and beta-amyloid (Abeta) to dense plaque-like deposits in the thalamus of rats subjected to transient middle cerebral artery occlusion (MCAO). Here, we investigated the underlying molecular effects of MCAO on APP processing and expression profiles of Abeta degrading enzymes in the cortex adjacent to the infarct (penumbra) and ipsilateral thalamus 2, 7 and 30 days after ischemic insult. Enhanced beta-amyloidogenic processing of APP and altered insulin degrading enzyme and neprilysin expression were observed in the thalamus, but not the penumbral cortex, 7 and 30 days after MCAO coinciding with increased calcium levels and beta-secretase (BACE) activity. Consecutively, increased BACE activity associated with depletion of BACE trafficking protein GGA3, suggesting a post-translational stabilization of BACE. These results demonstrate that focal cerebral ischemia leads to complex pathogenic events in the thalamus long after the initial insult.
Hiltunen
Mikko
M
Department of Neurology, University of Kuopio and Kuopio University Hospital, Kuopio, Finland. mikko.hiltunen@uku.fi
Mäkinen
Petra
P
Peräniemi
Sirpa
S
Sivenius
Juhani
J
van Groen
Thomas
T
Soininen
Hilkka
H
Jolkkonen
Jukka
J
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology*; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000378:metabolism*; D013997:Time Factors
D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D015260:Neprilysin; D007339:Insulysin; D002118:Calcium