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P3‐002: Interest of erp biomarker in clinical development of Alzheimer's disease therapeutics
Author(s) -
Bennys Karim,
Touchon Jacques,
Haddad Raphael,
Scart Gres Catherine
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.868
Subject(s) - p3b , p3a , biomarker , medicine , disease , drug development , oncology , latency (audio) , cognition , drug , event related potential , pharmacology , psychiatry , biochemistry , chemistry , engineering , electrical engineering
Background: Impaired glucose utilization and brain insulin resistance are markers of Alzheimer’s disease (AD). Beta-amyloid (Ab) 1-42, one of the pathological hallmarks of AD, could be a causative factor for this metabolic aberration. We have previously shown in hippocampus that Ab in physiological concentration degrades neuronal gamma oscillations (30-80Hz) by increasing CA3 pyramidal cell (PC) firing while de-synchronizing their action potentials, as well as altering the excitatory/ inhibitory balance in the microcircuit. Energy metabolism disturbance has been implicated in AD-related neuronal hyperexcitability. We set out to investigate whether the observed Ab effect is caused by energy metabolism disturbances. Insulin has been suggested to increase glucose uptake by promoting translocation and fusion of vesicles containing glucose transporters. We tested whether insulin is capable of preventing, or compensating for, the energy deficit caused by Ab, and thus recover normal cellular and network dynamics. Methods: Intracellular (patch) and extracellular (LFP) electrophysiological recordings were made in mouse hippocampal slices (p14-21). Data was analyzed using Axograph and Igor Pro. Results: Noninvasive (perforated patch) recordings of the resting membrane potential in PCs and synaptically activated parvalbumin-positive (PV+) fasting-spiking interneurons (FSN) revealed that Ab induces a resting membrane potential depolarization that was absent in invasive (whole-cell) recordings, where any loss of cellular ATP content is compensated for by ATP in the intracellular recording solution. This suggests that Ab-induced aberration in cellular and network characteristics is caused by depletion of ATP. Further experiments are needed to test whether alleviating ATP loss is a potential therapeutic strategy in AD. In our study we show that 20nM insulin when present prior to an acute extracellular application of 50nM Ab prevents Ab-induced membrane potential changes in PCs and activated PV+ FSNs, as well as preventing Ab-induced degradation of gamma oscillations. Conclusions: ATP depletion is likely to be caused by a disruption in glucose uptake by Ab and insulin is capable of compensating for such energy deficits. Further experiments are required to strengthen the direct role of insulin in enhancing glucose uptake to counter Ab-induced cytotoxicity.