Abstract
Amyloid-β peptide (Aβ) forms plaques in Alzheimer's disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target.
Highlights
Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disorder and the most common type of dementia in the elderly (Brookmeyer et al, 2007; Qiu et al, 2009)
We reported that a physiologically relevant concentration of Ab1–42 (Ab hereafter; Roher et al, 2009) reduces gamma oscillations in the hippocampal network by a desynchronization of pyramidal cells (PC) action potential (AP) and by a shift in the excitatory/inhibitory current balance (Kurudenkandy et al, 2014). Since endocannabinoids such as anandamide have been reported to have preventive properties against amyloid-b peptide (Ab)-induced impairments in WT and AD animal models in vitro and in vivo (Aso and Ferrer, 2014), we first investigated whether cannabinoid receptor (CB1 and CB2) activation could prevent the Ab-induced reduction of gamma oscillations
We found that compared to hippocampal slices in control conditions (100 nM Kainate acid (KA), power: 11.6 ± 1.7Â10À9 V2, n = 32, Figure 1A–B), Ab+WIN incubation resulted in significantly reduced gamma oscillation power (64.2 ± 9.0% reduction, power: 4.1 ± 1.0Â10À9 V2, n = 18, p = 0.0002 vs. control, Figure 1A–B), that was not significantly different from the reduced gamma power recorded in slices incubated with Ab only (59.4 ± 8.9% reduction, power: 4.7 ± 1.0Â10À9 V2, n = 20, p = 0.0007 vs control, Figure 1A–B)
Summary
Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disorder and the most common type of dementia in the elderly (Brookmeyer et al, 2007; Qiu et al, 2009). Gamma-frequency oscillations (30–80 Hz) have been suggested to underlie cognitive processes such as attention, sensory perception and memory (Tallon-Baudry and Bertrand, 1999; Sederberg et al, 2007; Fries, 2015) This is supported by the finding that gamma oscillations progressively decrease in AD patients in lock-step with advancing cognitive impairment (Herrmann and Demiralp, 2005; Koenig et al, 2005; de Haan et al, 2012). Endocannabinoids such as anandamide have been shown to possess protective properties against Ab-induced neuronal damage (Aso and Ferrer, 2014). Since anandamide has been reported to have protective properties against Ab-induced impairments in vitro and in vivo both in WT and AD animal models (Aso and Ferrer, 2014), we wanted to investigate the feasibility of cannabinoid and/or TrpV1 receptor activation as a therapeutic avenue for prevention of, and more importantly rescue from, Ab-induced degradation of cellular mechanisms and functional network dynamics important for cognition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
