Kevin Atchison

Age-dependent disruption in hippocampal theta oscillation in amyloid-β overproducing transgenic mice

Transgenic mice are used to model increased brain amyloid-β (Aβ) and amyloid plaque formation reflecting Alzheimers disease pathology. In our study hippocampal network oscillations, population spikes, and long-term potentiation (LTP) were recorded in APPswe/PS1dE9 (APP/PS1) and presenilin1 (PS1) transgenic and wild type mice at 2, 4, and 8 months of age under urethane anesthesia. Hippocampal theta oscillations elicited by brainstem stimulation were similar in wild type and PS1 mice at all age groups. In contrast, APP/PS1 mice showed an age-dependent decrease in hippocampal activity, characterized by a significant decline in elicited theta power and frequency at 4 and 8 months. Magnitudes of population spikes and long-term potentiation in the dentate gyrus were similar across groups at both 4 and 8 months. In APP/PS1 mice, soluble and insoluble Aβ, and hippocampal and cortical plaque load increased with age, and the disruption in hippocampal theta oscillation showed a significant correlation with plaque load. Our study shows that, using in vivo electrophysiological methods, early Aβ-related functional deficits can be robustly detected in the brainstem-hippocampus multisynaptic network.

Effects of the γ-secretase inhibitor semagacestat on hippocampal neuronal network oscillation

Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. One of the main obstacles is the poor predictive validity of our preclinical animal models. In the present study the effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical in vivo electrophysiological models. Recently disclosed Phase III findings on semagacestat indicated that Alzheimer’s disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since previous studies have shown that drugs impairing cognitive function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor antagonists, and nociceptin receptor agonists) disrupt or decrease power of elicited theta oscillation in the hippocampus, we tested the effects of acute and sub-chronic administration of semagacestat in this assay. Field potentials were recorded across the hippocampal formation with NeuroNexus multi-site silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta oscillation was elicited by electrical stimulation of the brainstem nucleus pontis oralis. Sub-chronic administration of semagacestat twice daily over 12 days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o. (per oral)] diminished power of elicited hippocampal theta oscillation. Acute, subcutaneous administration of semagacestat (100 mg/kg) produced a similar effect on hippocampal activity. We propose that the disruptive effect of semagacestat on hippocampal function could be one of the contributing mechanisms to its worsening of cognition in patients with AD. As it has been expected, both acute and sub-chronic administrations of semagacestat significantly decreased Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action of semagacestat in disrupting hippocampal oscillignificantly reduced braination.

Acute inhibition of gamma secretase lowers abeta dimer levels in plaque-bearing PSAPP mice

pathology appears to be due to LC degeneration and not simply low NA levels. This suggests that NA potentiates Ab toxicity. Indeed, catecholamines potentiate Ab misfolding and oxidative toxicity. For example, catecholamines both undergo autooxidation and increase Ab oxidative stress. Dopamine, a catecholamine, increases Ab misfolding into toxic oligomeric amyloid forms and it is likely that other catecholamines have a similar effect. Currently, the mechanism of how catecholamines catalyze Abmisfolding and augment oxidative toxicity is unknown.Methods:We have studied the effects of the catecholamines, dopamine, noradrenaline and adrenaline on Ab misfolding and oxidative stress in vitro using mass spectrometry, western blots, electron microscopy, protease protections assays and cell culture. Results: Our data demonstrates that all catecholamines increase Ab misfolding (likely oligomers) in vitro. Preliminary protease protection assay experiments and electron microscopy suggest that Ab oligomers are formed upon incubation with catecholamines. Additionally, we demonstrate that this process is enhanced by addition of the transition metal Cu and inhibited by EDTA and the antioxidant BHT. Structurally related compounds incompetent for autooxidation do not cause Ab misfolding or oxidative stress. The extent of catecholamine oxidation will be ascertained via LC/ MS and adduct formation with Ab via MALDI. Additionally, the effect of catecholamines on oxidative toxicity in vitro and in cultured cells will be ascertained. Conclusions: Thus, we have evidence that catecholamine neurotransmitters catalyze Ab misfolding and augment its oxidative stress in vitro. Extrapolation from this data suggests that catecholamines could play a role in Ab pathogenesis in AD.