Tesis doctoral de Manuel Rodríguez Perdigón
-in ad postmortem brain samples central insulin resistance was observed, as reflected by decreased expression of insulin receptor (ir) mrna and reduced pakt and perk2 protein levels. -high fat diet induced insulin resistance model showed both peripheral (assessed by high levels of peripheral ketone bodies and high homa index) as well as central insulin resistance (assessed by decreased expression of ir, irs-1 and pakt and high levels of ketone bodies). -both in postmortem human brains of ad and in an experimental model of insulin resistance, the glutamatergic terminal marker vglut1 expression was diminished. -treatment with ketone bodies decreased glutamate release in primary cell cultures in a concentration dependent manner. These results suggest that elevated levels of ketone bodies associated with an insulin resistance situation promotes decreases in vglut1 expression and glutamate release, contributing to the glutamatergic deficits observed in ad. -in ad brain samples, increased jnk activity associated with alterations in insulin signaling was observed. In an experimental model of insulin resistance, the specific jnk inhibitor (d-jnki-1) reversed the central alterations in insulin signaling markers as well as the decreases in vglut1 levels. -in high β-amyloid peptide level models, such as tg2576 mice primary cell culture or wild type mice primary cell cultures treated with aβ1-42, decreased vglut1 expression and reduced glutamate release was observed. In human ad brain cortex samples, it has been also observed a decrease in vglut1 expression which correlated statistically with increased levels of aβ1-42 and senile plaques. This decrease in vglut1 expression did not correlate with cognitive decline, measured by mmse. -in tg2576 mice, an experimental ad model characterized by amyloid pathology, a decrease in vglut1 levels at 8 months of age was observed that is not accompanied by cognitive impairment in the morris water maze task. These results suggest that initially the loss of glutamatergic terminals does not appear to be decisive for the development of cognitive deficits in ad. Aβ administration in vglut1 +/- mice caused an increased microglial and astrocytic reactivity (using iba1 and gfap markers respectively) in the hippocampus. These data suggest that vglut1 terminals loss may increase the vulnerability to subsequent hippocampal insults. -diet supplementation with lipoic acid reversed the cognitive deficits associated to the experimental model of insulin resistance, decreased the expression of peripheral (homa index and insulin levels) and increased central insulin resistance markers (pir, pakt, perk), reversed increased levels of ketone bodies (in plasma and hippocampus) and increased expression of vglut1. Therefore, it is proposed that lipoic acid may be a potential treatment to reverse the insulin resistance and altered expression of vglut1 that could underlie in ad pathogenesis. -the results obtained the present study support the idea that in a situation of insulin resistance, metabolism shifts to the production of ketone bodies and acting on vglut1 could enhance the glutamatergic deficit in ad. Insulin resistance could be related to the action of aβ on the insulin receptor. Although initially this glutamatergic impairment does not seem to be directly related to cognitive decline in ad, the decreased expression of vglut1 could facilitate other pathological mechanisms, such as neuroinflammation, and it is this complex combination of factors which could lead to the cognitive deficits associated to ad.
Datos académicos de la tesis doctoral «Regulación del transportador de glutamato 1 (vglut1) en situaciones de resistencia a insulina: implicación en la enfermedad de alzheimer«
- Título de la tesis: Regulación del transportador de glutamato 1 (vglut1) en situaciones de resistencia a insulina: implicación en la enfermedad de alzheimer
- Autor: Manuel Rodríguez Perdigón
- Universidad: Navarra
- Fecha de lectura de la tesis: 08/09/2015
Dirección y tribunal
- Director de la tesis
- María Javier Ramirez Gil
- Tribunal
- Presidente del tribunal: María Jesús Moreno aliaga
- antoni Camins espuny (vocal)
- Francisco Javier Gil bea (vocal)
- paul Francis (vocal)