Abstract
Altered hypoxia-inducible factor-alpha (HIF-α) activity may have significant consequences in the hippocampus, which mediates declarative memory, has limited vascularization, and is vulnerable to hypoxic insults. Previous studies have reported that neurovascular coupling is reduced in aged brains and that diseases which cause hypoxia increase with age, which may render the hippocampus susceptible to acute hypoxia. Most studies have investigated the actions of HIF-α in aging cortical structures, but few have focused on the role of HIF-α within aged hippocampus. This study tests the hypothesis that aging is associated with impaired hippocampal HIF-α activity. Dorsal hippocampal sections from mice aged 3, 9, 18, and 24 months were probed for the presence of HIF-α isoforms or their associated gene products using immunohistochemistry and fluorescent in situ hybridization (fISH). A subset of each age was exposed to acute hypoxia (8% oxygen) for 3 h to investigate changes in the responsiveness of HIF-α to hypoxia. Basal mean intensity of fluorescently labeled HIF-1α protein increases with age in the hippocampus, whereas HIF-2α intensity only increases in the 24-month group. Acute hypoxic elevation of HIF-1α is lost with aging and is reversed in the 24-month group. fISH reveals that glycolytic genes induced by HIF-1α (lactose dehydrogenase-a, phosphoglycerate kinase 1, and pyruvate dehydrogenase kinase 1) are lower in aged hippocampus than in 3-month hippocampus, and mRNA for monocarboxylate transporter 1, a lactose transporter, increases. These results indicate that lactate, used in neurotransmission, may be limited in aged hippocampus, concurrent with impaired HIF-α response to hypoxic events. Therefore, impaired HIF-α may contribute to age-associated cognitive decline during hypoxic events.
Highlights
Methods to delay cognitive decline associated with aging and lengthen “health-span” have become a primary concern as the global average life-span continues to increase [1]
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Transcription of genes which facilitate lactate production, lactose dehydrogenase A (Ldha), pyruvate dehydrogenase kinase 1 (Pdk1), and Phosphoglycerate kinase 1 (Pgk1), are suppressed in aged hippocampus (Figure 6A–D). These results suggest that mild chronic hypoxia may be present in aged hippocampus, as well as possibly altered gene transcription by HIF-α
Summary
Methods to delay cognitive decline associated with aging and lengthen “health-span” (the period of time an individual lives disease-free) have become a primary concern as the global average life-span continues to increase [1]. The inability to efficiently adapt to hypoxia, may underlie slower memory recall observed in aging, and chronic hypoxia due to age-related diseases may dysregulate protective molecular responses, predisposing those individuals to the onset of dementias following acute hypoxic events [5]. Because the dorsal hippocampus is integral to declarative memory [26], dysregulation of HIF-α within the hippocampus may be of particular concern in the context of cognitive aging, especially with chronic and/or acute hypoxia. This study investigates the spatial expression of HIF-1α and HIF-2α and their gene products to determine whether one or more subregions of the hippocampus are more or less impacted by changes in HIF-α activity during aging.
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