Abstract
BackgroundTranslational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment.MethodsBrainstem nucleus pontis oralis stimulation-induced hippocampal oscillations were recorded under urethane anesthesia in adult (6-month-old) and aged (12-month-old) TgF344-AD and wild-type rats. Spontaneous cortical activity was monitored in a cohort of freely behaving aged rats implanted with frontal and occipital cortical electroencephalography (EEG) electrodes.ResultsSubcutaneous administration of donepezil significantly augmented stimulation-induced hippocampal theta oscillation in aged wild-type rats and both adult and aged TgF344-AD rats, which have been previously shown to have diminished response to nucleus pontis oralis stimulation. Moreover, in adult TgF344-AD rats, donepezil also significantly increased theta phase-gamma amplitude coupling in the hippocampus during stimulation. However, neither of these effects were significantly changed in adult wild-type rats. Under freely behaving conditions, donepezil treatment had the opposite effect on cortical oscillatory connectivity in TgF344-AD and wild-type rats, and it reduced the occurrence of high-voltage spindle activity in TgF344-AD rats.ConclusionsTogether, these results imply that pharmacologically enhancing cholinergic tone with donepezil could partially reverse oscillatory abnormalities in TgF344-AD rats, which is in line with its clinical effectiveness in AD patients. Therefore, our study suggests good translational opportunities for these neurophysiological signals recorded in TgF344-AD rats, and their application could be considered in drug discovery efforts for developing therapies with disease-modifying potential.
Highlights
Translational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition
Consistent with our recent report on TgF344-AD rats [13], stimulus-response analysis showed a reduction in hippocampal oscillatory activity with a diminished theta power in both adult and aged TgF344-AD rats compared with their respective WT rats
Both adult and aged WT and TgF344-AD rats responded to systemic subcutaneous administration of donepezil at the dose of 1 mg/kg (F(3,18) = 1.058; p = 0.39 two-way mixed design analysis of variance (ANOVA)), significantly increasing stimulation-induced theta power (Fig. 1a) over the course of experiment (F(44,792) = 7.197; p = 0.0005, two-way mixed design ANOVA)
Summary
Translational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. A significant setback partly lies in our still insufficient understanding of the complex pathophysiology of AD, causing lack of tractable biomarkers that would reliably measure disease progression and response to therapy Another factor hampering successful translation from bench to bedside is that the transgenic animal models of AD used in the early phases of drug discovery, though capturing some pathological aspects of disease (e.g., amyloid plaques and neurofibrillary tangles), often do not faithfully simulate critical interactions between processes underlying aging and the development of AD traits observed in humans [2]. In TgF344-AD rats, cortical EEG revealed enhanced neuronal excitability with significantly increased expression of high-voltage spindles (HVSs), resembling epileptic absence seizure-like activity Along with these changes, TgF344-AD rats exhibited impairments in sensory information processing as revealed by tests which are used in clinical practice [13]. Many of these functional abnormalities observed in TgF344-AD rats mirror alterations observed in AD patients [10, 16, 17]
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