Brain Insulin Resistance in the Experimental TgSwDI Mouse Model of Alzheimer's Disease
Translated title
Hjerne insulin resistens i en eksperimentel TgSwDI musemodel for Alzheimers sygdom
Author
Jensen, Kathrine Overgaard
Term
4. term
Publication year
2025
Submitted on
2025-05-28
Pages
78
Abstract
Alzheimers sygdom mangler fortsat effektive behandlinger, og hjernens insulinresistens er foreslået som en medvirkende mekanisme. Dette projekt undersøger derfor insulinreceptoren (INSR) og insulinlignende vækstfaktor 1-receptoren (IGF-1R) i den eksperimentelle TgSwDI-musemodel for at belyse signaleringen ved blod-hjerne-barrieren (BBB) og vurdere, om forholdet mellem INSRα-A og INSRα-B kan fungere som markør for hjernens insulinresistens. Ved hjælp af en kapillær-depletionsmetode (valideret med cresyl violet-farvning) blev total hjerne, isolerede kapillærer og kapillær-depleterede hjernefraktioner analyseret. Western blot blev anvendt til at måle proteinindholdet af INSRα-isoformer og IGF-1R i TgSwDI-mus (18 og 30 måneder) og vildtype-mus (12 måneder), og fosforyleringsniveauer af INSR og IGF-1R blev vurderet efter intraperitoneal injektion af insulin eller saltvand i TgSwDI-mus (15 måneder) og vildtyper (12 måneder). INSRα-A og INSRα-B var overvejende beriget i de isolerede kapillærfraktioner, men et forhøjet INSRα-A/B-forhold ved BBB kunne ikke påvises. På grund af lave proteinkoncentrationer i hjernefraktionerne kunne forskelle i IGF-1R mellem kapillærer og kapillær-depleterede fraktioner ikke afgøres, mens IGF-1R-proteinindholdet samlet set var højere i TgSwDI-mus end i vildtyper. Der blev ikke fundet signifikante forskelle i fosforyleringen af INSR og IGF-1R mellem TgSwDI- og vildtype-mus. Samlet peger resultaterne på BBB-lokaliseret berigelse af insulinsignaleringens komponenter, men de reproducerer ikke det foreslåede INSRα-A/B-forhold som biomarkør for hjernens insulinresistens i denne model og understreger behovet for yderligere sammenlignende studier.
Alzheimer’s disease lacks effective treatments, and brain insulin resistance has been proposed as a contributing mechanism. This project therefore examines the insulin receptor (INSR) and insulin-like growth factor 1 receptor (IGF-1R) in the experimental TgSwDI mouse model to probe signaling at the blood–brain barrier (BBB) and assess whether the INSRα-A to INSRα-B ratio could serve as a marker of brain insulin resistance. Using a capillary depletion approach (validated by cresyl violet staining), total brain, isolated capillaries, and capillary-depleted brain fractions were analyzed. Western blots quantified INSRα isoforms and IGF-1R in TgSwDI mice (18 and 30 months) and wild-type mice (12 months), and phosphorylation of INSR and IGF-1R was assessed after intraperitoneal insulin or saline in TgSwDI mice (15 months) and wild types (12 months). INSRα-A and INSRα-B were predominantly enriched in isolated capillary fractions, but an elevated INSRα-A/B ratio at the BBB was not observed. Due to low protein concentrations in brain fractions, differences in IGF-1R between capillaries and capillary-depleted fractions could not be determined; overall, IGF-1R protein content was higher in TgSwDI mice than in wild types. No significant differences in INSR or IGF-1R phosphorylation were detected between TgSwDI and wild-type mice. Together, the findings indicate BBB-localized enrichment of insulin signaling components but do not replicate the proposed INSRα-A/B ratio as a biomarker of brain insulin resistance in this model, highlighting the need for further comparative studies.
[This abstract was generated with the help of AI]
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