Chronic synaptic insulin resistance after traumatic brain injury abolishes insulin protection from amyloid beta and tau oligomer-induced synaptic dysfunction

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Abstract

Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD), although the mechanisms contributing to this increased risk are unknown. Insulin resistance is an additional risk factor for AD whereby decreased insulin signaling increases synaptic sensitivity to amyloid beta (Aβ) and tau. Considering this, we used rats that underwent a lateral fluid percussion injury at acute and chronic time-points to investigate whether decreased insulin responsiveness in TBI animals is playing a role in synaptic vulnerability to AD pathology. We detected acute and chronic decreases in insulin responsiveness in isolated hippocampal synaptosomes after TBI. In addition to assessing both Aβ and tau binding on synaptosomes, we performed electrophysiology to assess the dysfunctional impact of Aβ and tau oligomers as well as the protective effect of insulin. While we saw no difference in binding or degree of LTP inhibition by either Aβ or tau oligomers between sham and TBI animals, we found that insulin treatment was able to block oligomer-induced LTP inhibition in sham but not in TBI animals. Since insulin treatment has been discussed as a therapy for AD, this gives valuable insight into therapeutic implications of treating AD patients based on one’s history of associated risk factors.

Original languageEnglish (US)
Article number8228
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Amyloid
Insulin Resistance
Insulin
Alzheimer Disease
Synaptosomes
Percussion
Electrophysiology
Therapeutics
Traumatic Brain Injury
Pathology
Wounds and Injuries

ASJC Scopus subject areas

  • General

Cite this

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title = "Chronic synaptic insulin resistance after traumatic brain injury abolishes insulin protection from amyloid beta and tau oligomer-induced synaptic dysfunction",
abstract = "Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD), although the mechanisms contributing to this increased risk are unknown. Insulin resistance is an additional risk factor for AD whereby decreased insulin signaling increases synaptic sensitivity to amyloid beta (Aβ) and tau. Considering this, we used rats that underwent a lateral fluid percussion injury at acute and chronic time-points to investigate whether decreased insulin responsiveness in TBI animals is playing a role in synaptic vulnerability to AD pathology. We detected acute and chronic decreases in insulin responsiveness in isolated hippocampal synaptosomes after TBI. In addition to assessing both Aβ and tau binding on synaptosomes, we performed electrophysiology to assess the dysfunctional impact of Aβ and tau oligomers as well as the protective effect of insulin. While we saw no difference in binding or degree of LTP inhibition by either Aβ or tau oligomers between sham and TBI animals, we found that insulin treatment was able to block oligomer-induced LTP inhibition in sham but not in TBI animals. Since insulin treatment has been discussed as a therapy for AD, this gives valuable insight into therapeutic implications of treating AD patients based on one’s history of associated risk factors.",
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