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

• Published in: Frontiers in cellular neuroscience 2014-01, Vol.8, p.1-1
• Main Authors: Lonati, Elena, Brambilla, Anna, Milani, Chiara, Masserini, Massimo, Palestini, Paola, Bulbarelli, Alessandra
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid precursor protein; Amyloidogenesis; Cell culture; Central nervous system; cerebrovascular deficiencies; Cognitive ability; Dementia; Enzymatic activity; Gene expression; Glycogen; Glycogen synthase kinase 3; GSK-3β; HIF-1α; hippocampal neurons; Hippocampus; Hypotheses; Hypoxia; Hypoxia-inducible factor 1; Immunoglobulins; Immunoprecipitation; Ischemia; Kinases; L-Lactate dehydrogenase; Lactic acid; Neoplasia; Neurodegeneration; Neurodegenerative diseases; Neuroscience; Older people; Oxygen; Phosphorylation; Pin1; Pin1 protein; Prostate cancer; Proteasomes; Protein turnover; Proteins; Risk factors; Secretase; Transcription factors; β-Site APP-cleaving enzyme 1
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2014.00001

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-1α 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-1α protein level is known to be regulated by von Hippel-Lindau (VHL) ubiquitin-proteasome system, it has been recently suggested that glycogen synthase kinase-3β (Gsk-3β) promotes a VHL-independent HIF-1α degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1α degradation might be mediated by a synergic action of Gsk-3β and peptidyl-prolyl cis/trans isomerase (Pin1). In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD), HIF-1α protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of lactate dehydrogenase (LDH) and β-secretase 1 (BACE1) protein expression (70 and 140% respectively). Interestingly the Pin1 activity decreases about 40-60% and Pin1(S16) inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1α/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3β inhibitors their interaction is reduced in parallel to an increase of HIF-1α protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1α might be due to Pin1 binding ability and activity reduction which affects HIF-1α degradation: an event that may highlight the relevance of ischemia/HIF-1α as a risk factor in AD pathogenesis.