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-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 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-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.
Highlights
Alzheimer’s disease (AD) is a multifactor neurodegenerative pathology affecting the elderly population
We observed that lactate dehydrogenase (LDH) expression increased about 70% already at R 1 h, slightly decreasing during overnight, while β-secretase 1 (BACE1) protein level significantly increased during o/n, reaching 150% of increment (Figure 1A)
Protein levels of its hypoxia responsive α subunit (HIF-1α) are finely regulated by degradation through ubiquitin-proteasome system that may be induced by hydroxylation (VHL-mediated) and as recently suggested by phosphorylation (Gsk-3β-mediated; Flügel et al, 2007, 2012)
Summary
Alzheimer’s disease (AD) is a multifactor neurodegenerative pathology affecting the elderly population. The pathogenesis of sporadic late-onset AD has not been identified, but further studies support that cerebral ischemia/stroke significantly increases AD. It has been suggested that cerebral hypoperfusion causing neuronal damage in vulnerable brain areas (Koistinaho and Koistinaho, 2005; Zhang et al, 2007) may serve as a basis for some cases of dementia after stroke (Ogunshola and Antoniou, 2009). A large percentage of hypoxic responses are controlled by hypoxia-inducible transcription factor-1 (HIF-1; Webb et al, 2009) whose involvement in neurodegenerative disorders is becoming widely accepted, its role may greatly depend on whether it is the cause or the consequence in disease progression (Ogunshola and Antoniou, 2009; Bulbarelli et al, 2012).
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