Up-regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease.
Gene expression throughout the different stages of Alzheimer's disease was analysed in samples from cerebral cortex. The gene encoding the voltage-gated potassium channel Kv3.4 was already overexpressed in early stages of the disease, and in advanced stages Kv3.4 was present at high levels in neurodegenerative structures. This subunit regulates delayed-rectifier currents, which are primary determinants of spike repolarization in neurones. In unique samples from a patient with Alzheimer's disease whose amount of amyloid plaques was decreased by beta amyloid immunization, Kv3.4 was overexpressed. The channel subunit was expressed in the neuropil, in the remaining conventional plaques in the frontal cortex and in collapsed plaques in the orbitary cortex. Therefore, amyloid deposition in plaques does not seem to be responsible for the increase in Kv3.4 levels. Nevertheless, Kv3.4 up-regulation is related to amyloid pathology, given that transgenic mice with the Swedish mutation of amyloid precursor protein showed increased expression of Kv3.4. Up-regulation of voltage-gated potassium channel subunits alters potassium currents in neurones and leads to altered synaptic activity that may underlie the neurodegeneration observed in Alzheimer's disease. Thus, Kv3.4 likely represents a novel therapeutic target for the disease.
Angulo
Ester
E
Department of Biochemistry and Molecular Biology, School of Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain.
Noé
Véronique
V
Casadó
Vicent
V
Mallol
Josefa
J
Gomez-Isla
Teresa
T
Lluis
Carmen
C
Ferrer
Isidre
I
Ciudad
Carlos J
CJ
Franco
Rafael
R
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051670:Shaw Potassium Channels; D015854:Up-Regulation / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; C492015:KCNC4 protein, human; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D012333:RNA, Messenger; D051670:Shaw Potassium Channels