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.

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats

“…Our standard protocol was used as previously described [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ] with the following modifications for recording low frequency stimulation long-term depression (LFS-LTD). Briefly, mice were deeply anesthetized with isoflurane (Piramal Pharma Solutions, Lexington, KY, USA) and transcardially perfused with ~30 mL of room temperature carbogenated (95% O 2 and 5% CO 2 gas mixture) NMDG-artificial cerebrospinal fluid (aCSF) (in mM 93 N -Methyl- d -Gluconate, 2.5 KCl, 1.2 NaH 2 PO 4 , 30 NaHCO 3 , 20 C 8 H 18 N 2 O 4 S, 25 C 6 H 12 O 6 , 5 C 6 H 7 O 6 Na, 2 CH 4 N 2 S, 3 C 3 H 3 NaO 3 , 10 MgSO 4 ,7H 2 O, 0.5 CaCl 2 ,2H 2 O, 12 C 5 H 9 NO 3 S, pH 7.4).…”

Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology

“…RIPA buffer (catalog #9806S, Cell Signaling Technology) with 1% protease and phosphatase cocktail inhibitors was used to lysate tissues and synaptosomes to obtain the total protein fraction and the synaptosomal fraction, respectively. The synaptosomes were isolated from the cortical tissues by using a method very well established in our laboratory ( Franklin and Taglialatela, 2016 ; Comerota et al, 2017 ; Franklin et al, 2019 ). Briefly, we lysed the cortical tissues by using the SynPER lysis buffer (catalog #87793, Thermo Fisher Scientific) with 1% protease and phosphatase cocktail inhibitors.…”

Role of Insulin in Neurotrauma and Neurodegeneration: A Review

“…In addition, catecholamines stimulate islet beta cells to increase glucagon production, resulting in decreased insulin secretion ( Halter et al, 1984 ). Reduced insulin sensitivity and signaling at synapses has been observed after TBI in animal studies, indicating that insulin resistance may occur and impair the body’s ability to maintain glucose homeostasis ( Karelina et al, 2016 ; Franklin et al, 2019 ). The mechanism behind insulin resistance is not currently known, but may be related to post-injury excitotoxicity described in the previous section.…”

“…Reduced sensitivity or resistance to insulin actions, via downregulation or loss of IR or reduced activity of insulin signaling pathway, contributes to worsened outcome in several neurological conditions, further highlighting the importance of insulin in the CNS. Insulin resistance is observed in various instances of neurotrauma ( Karelina and Weil, 2016 ; Franklin et al, 2019 ; Kim et al, 2019 ) and neurodegenerative diseases ( Diehl et al, 2017 ; de la Monte, 2012 ).…”