Abstract
Background and Purpose: Neurodegenerative diseases are associated with metabolic disturbances. Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer’s disease (AD), epilepsy, Leigh’s syndrome, and diabetes-associated cognitive decline. However, the exact role of PDHA1 deficiency in neurodegenerative diseases remains to be elucidated. In this study, we explored the effect of PDHA1 deficiency on cognitive function and its molecular mechanism.Methods: A hippocampus-specific Pdha1 knockout (Pdha1–/–) mouse model was established, and behavioral tests were used to evaluate the cognitive function of mice. Transmission electron microscopy (TEM) was performed to observe the morphological changes of the hippocampus. The lactate level in the hippocampus was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition.Results: Pdha1 knockout damaged the spatial memory of mice and led to the ultrastructural disorder of hippocampal neurons. Lactate accumulation and abnormal lactate transport occurred in Pdha1–/– mice, and the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway was inhibited.Conclusion: Lactate accumulation caused by PDHA1 deficiency in the hippocampus may impair cognitive function by inhibiting the cAMP/PKA/CREB pathway.
Highlights
Metabolic insufficiency occurs in neurodegenerative diseases, including Alzheimer’s disease (AD; Turner, 2021)
The hippocampi of mice were extracted to evaluate the expression of Pyruvate dehydrogenase E1 component subunit alpha (PDHA1)
We observed that the expression of PDHA1 in the hippocampal protein extracts from Pdha1−/− mice decreased by ∼65% (Figure 1C)
Summary
Metabolic insufficiency occurs in neurodegenerative diseases, including Alzheimer’s disease (AD; Turner, 2021). The clinical symptoms of PDC deficiency range from fatal lactic acidosis or progressive neuromuscular injury to chronic neurodegeneration (Robinson, 2006; Imbard et al, 2011; Patel et al, 2012; PavluPereira et al, 2021). These symptoms suggest that the nervous system is susceptible to perturbations in PDC activity due to its dependence on carbohydrate metabolism (Gray et al, 2014). Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer’s disease (AD), epilepsy, Leigh’s syndrome, and diabetes-associated cognitive decline. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition
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