Differential effects of unaggregated and aggregated amyloid β protein (1–40) on K⁺ channel currents in primary cultures of rat cerebellar granule and cortical neurones

Abstract

The effects of amyloid b protein on voltage-gated K 1 channel currents were studied using the whole-cell patch-clamp technique. The 1±40 amino acid form of amyloid b protein was applied to primary cultures of rat cerebellar granule and cortical neurones for 24 h. Both the unaggregated and aggregated forms of the peptide, which have differing biological activities, were used. In cerebellar granule neurones, 24-h pre-incubation with 1 mM unaggregated amyloid b protein resulted in a 60% increase in the`A'-type component of K 1 current. Increased delayed recti®er activity was Cd 21 -sensitive and was presumed to be secondary to an increase in voltage-gated Ca 21 channel current activity. Unaggregated amyloid b protein had no effect on any component of the K 1 channel current in cortical neurones. One micromolar of aggregated amyloid b protein had no effect on K 1 channel current in either cell type but reduced cell survival within 24 h as measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays. The unaggregated form of amyloid b protein had no neurotoxic effects when applied to either neurone type for up to 72 h. These data indicate that the unaggregated, nonpathological form of amyloid b protein causes changes in the ion channel function of neurones, possibly re¯ecting a physiological role for the peptide.

Prion protein and Alzheimer disease

“…21 While Aβ is commonly thought of as the main toxic agent in AD, there is emerging evidence of a normal physiological role for the peptide in the regulation of neuronal calcium and potassium channel currents. 22,23 This, therefore, indicates that Aβ should only be considered as a toxic agent when levels increase as a result of an imbalance in its production and degradation/ clearance, such as occurs in AD.…”

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

“…Recent research has demonstrated that changes in K ϩ channel activity play a major pathogenetic role in many neurodegenerative disorders, including Alzheimer's disease (AD). In fact, ␤-amyloid fragments (A␤), generated upon processing of the integral membrane amyloid precursor protein (Suh and Checler, 2002), alter the properties of K ϩ currents in mammalian neurons (Jalonen et al, 1997;Yu et al, 1998;Jhamandas et al, 2001;Ramsden et al, 2001;Pannaccione et al, 2005). Furthermore, a study performed on SN56 cells, a cholinergic cell line from rat, reported that treatment with A␤ increased the amount of delayed rectifier K ϩ currents and increased cell death (Colom et al, 1998).…”

The MiRP2-Kv3.4 Potassium Channel: Muscling In on Alzheimer's Disease: Fig. 1.

“…Ramsden et al (2001) noted that longterm exposure of rat cerebellar granule neurons to unaggregated A␤ 1-40 led to an increase in both the inactivating I KA current (peak-end current) and I KV (end current), whereas acute administration had no effect. Increased current was also observed using a protocol employing a Ϫ50 mV prepulse, which removes the majority of the I KA current component.…”