Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gali, C.
Mechanisms governing changes in cerebrovascular insulin signaling in Alzheimer’s disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 150
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Groschner Klaus
- Panzenboeck Ute
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- Abstract:
- Cerebral insulin signaling impairment has been identified in Alzheimer’s disease (AD) subjects and AD mouse models. In brain, insulin signaling is key for neuronal growth, memory consolidation and long-term potentiation. Low-density lipoprotein receptor-related protein-1 (LRP-1) was shown to modulate insulin signal-ing by dimerizing with insulin receptor beta (IR-β) upon insulin stimulation, and LRP-1 deletion is known to impair IR-β receptor levels thereby hindering insulin mediated responses in mice. Both LRP-1 and IR-β are expressed in cerebromicrovascular endothelial cells which constitute the blood-brain barrier (BBB). Recent evidence shows that insulin regulates surface expression of LRP-1 in hepatocytes and at the BBB and could possibly modulate Aβ clearance from the brain and periphery. Even though several studies reported changes in brain insu-lin signaling in AD, cerebrovascular endothelial modulation of insulin signaling, mediated by IR-β and LRP-1 in AD is not well understood. In the present thesis we found a significant impairment in brain and cerebromicrovascular IR-β and LRP-1 levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) mice when compared to age matched NTg mice, which in further conse-quence affected insulin mediated signaling response pathways. Alterations observed in brain and cerebromicrovascular IR-β and LRP-1 levels correlated with elevated LC3B levels in 3XTg-AD mice indicating activation of autophagy. High-fat diet (HFD) feeding reduced cerebral and hepatic LRP-1 levels and enhanced cerebral Aβ burden without showing considerable effects on cerebromicrovascu-lar LRP-1 and IR-β levels. Subsequent in vitro studies using porcine brain capil-lary endothelial cells (pBCEC) revealed that treatment with Aβ1-40 or Aβ1-42 im-paired LRP-1 and IR-β receptor levels and hampered their interaction in BCEC, thereby plummeting insulin mediated signaling. Subsequent mechanistic exploration confirmed that Aβ treatment enhanced the autophagy-lysosomal degradation of LRP-1 and IR-β receptors in pBCEC. Using siRNA approach in pBCEC, we identified that LRP-1 deletion post-translationally hampered IR-β levels and in turn reduced insulin-mediated response pathways at the BBB. Our findings indicate that cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby weakening cerebromicrovascular (and cerebral) insulin effects.