Rab6 is increased in Alzheimer's disease brain and correlates with endoplasmic reticulum stress.
Alzheimer's disease (AD) is characterized by deposits of aggregated proteins. Accumulation of aggregation-prone proteins activates protein quality control mechanisms, such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER). We previously reported upregulation of the UPR marker BiP in AD brain. In this study, we investigated the small GTPase Rab6, which is involved in retrograde Golgi-ER trafficking and may function as a post-ER quality control system. Using immunohistochemistry and semiquantitative Western blotting, the expression of Rab6 was analysed in hippocampus, entorhinal and temporal cortex of 10 AD patients and six nondemented control subjects. Rab6 is upregulated in AD temporal cortex from Braak stage 3/4, the same stage that UPR activation is found. We observe increased neuronal Rab6 immunoreactivity in all brain areas examined. Although some neurones show colocalization of immunoreactivity for Rab6 and hyperphosphorylated tau, strong Rab6 staining does not colocalize with tangles. We find a highly significant correlation between the Rab6 and BiP levels. In vitro data show that Rab6 is not upregulated as a result of UPR activation or proteasome inhibition indicating an independent regulatory mechanism. Our data suggest that ER and post-ER protein quality control mechanisms are activated early in the pathology of AD.
Scheper
W
W
Neurogenetics Laboratory, Academic Medical Center, Amsterdam, The Netherlands. w.scheper@amc.uva.nl
Hoozemans
J J M
JJ
Hoogenraad
C C
CC
Rozemuller
A J M
AJ
Eikelenboom
P
P
Baas
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis*; D016875:tau Proteins / Q000378:metabolism
C094135:Rab6 protein; D016875:tau Proteins; D020691:rab GTP-Binding Proteins