Aetiology of neurodegenerative mechanisms underlying Alzheimer’s disease (AD) are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke) has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1). Thus alterations of oxygen responsive HIF-1a subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to amyloid precursor protein (APP) amyloidogenic metabolism. Although HIF-1a protein level is known to be regulated by von Hippel-Lindau (VHL) ubiquitin-proteasome system, it has been recently suggested that glycogen synthase kinase-3b (Gsk-3b) promotes a VHL-independent HIF-1a degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1a degradation might be mediated by a synergic action of Gsk-3b and peptidyl-prolyl cis/trans isomerase (Pin1). In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD), HIF-1a protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of lactate dehydrogenase (LDH) and b-secretase 1 (BACE1) protein expression (70 and 140% respectively). Interestingly the Pin1 activity decreases about 40–60% and Pin1S16 inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1a/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3b inhibitors their interaction is reduced in parallel to an increase of HIF-1a protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1a might be due to Pin1 binding ability and activity reduction which affects HIF-1a degradation: an event that may highlight the relevance of ischemia/HIF-1a as a risk factor in AD pathogenesis.

Lonati, E., Brambilla, A., Milani, C., Masserini, M., Palestini, P., & Bulbarelli, A. (2014). Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer’s disease risk factor. FRONTIERS IN CELLULAR NEUROSCIENCE, 8, 1-11 [10.3389/fncel.2014.00001].

Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer’s disease risk factor

LONATI, ELENA RITA;BRAMBILLA, ANNA;MILANI, CHIARA;MASSERINI, MASSIMO ERNESTO;PALESTINI, PAOLA NOVERINA ADA;BULBARELLI, ALESSANDRA
2014

Abstract

Aetiology of neurodegenerative mechanisms underlying Alzheimer’s disease (AD) are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke) has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1). Thus alterations of oxygen responsive HIF-1a subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to amyloid precursor protein (APP) amyloidogenic metabolism. Although HIF-1a protein level is known to be regulated by von Hippel-Lindau (VHL) ubiquitin-proteasome system, it has been recently suggested that glycogen synthase kinase-3b (Gsk-3b) promotes a VHL-independent HIF-1a degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1a degradation might be mediated by a synergic action of Gsk-3b and peptidyl-prolyl cis/trans isomerase (Pin1). In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD), HIF-1a protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of lactate dehydrogenase (LDH) and b-secretase 1 (BACE1) protein expression (70 and 140% respectively). Interestingly the Pin1 activity decreases about 40–60% and Pin1S16 inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1a/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3b inhibitors their interaction is reduced in parallel to an increase of HIF-1a protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1a might be due to Pin1 binding ability and activity reduction which affects HIF-1a degradation: an event that may highlight the relevance of ischemia/HIF-1a as a risk factor in AD pathogenesis.
Articolo in rivista - Articolo scientifico
Scientifica
Alzheimer’s disease, cerebrovascular deficiencies, hippocampal neurons, Pin1, HIF-1a, GSK-3b, oxygen glucose deprivation
English
Lonati, E., Brambilla, A., Milani, C., Masserini, M., Palestini, P., & Bulbarelli, A. (2014). Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer’s disease risk factor. FRONTIERS IN CELLULAR NEUROSCIENCE, 8, 1-11 [10.3389/fncel.2014.00001].
Lonati, E; Brambilla, A; Milani, C; Masserini, M; Palestini, P; Bulbarelli, A
File in questo prodotto:
File Dimensione Formato  
Frontiers Cel Neurosci 2014.pdf

accesso aperto

Dimensione 1.21 MB
Formato Adobe PDF
1.21 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/50421
Citazioni
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 20
Social impact