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"... Patients with type 2 diabetes are nearly three times as likely to develop cognitive impairment, and up to one in five patients over 60 develops dementia. Despite this, the cellular mechanisms linking high blood sugar to cognitive decline have been difficult to isolate.
A new study ... combines patient data with mouse experiments to map a pathway connecting elevated glucose to the death of memory-forming neurons. In a cohort of more than 2000 older adults with type 2 diabetes followed for nearly 5 years, higher levels of lactate, a byproduct of how the body processes glucose, were associated with an increased risk of mild cognitive impairment.
To probe causality, the researchers turned to mice, focusing on neurons from the hippocampus, a region central to learning and memory.
Under high glucose conditions, these neurons overstabilized a protein called Creb3, which, in turn, ramped up production of an enzyme that generates lactate. The excess piled up, overwhelming the cell’s energy systems and disrupting mitochondria, eventually triggering neuronal death.
These changes were then reflected in behavior; in tests like the Morris water maze, which measures spatial learning and memory, diabetic mice performed worse than controls.
Interrupting this pathway with a specially designed peptide reversed the damage. In diabetic mice, the treatment lowered lactate levels, protected hippocampal neurons, and improved performance on memory tests. Because the peptide can cross the blood-brain barrier, it points to a potential strategy for slowing or preventing diabetes-related cognitive decline. ..."
From the editor's summary and abstract:
"Editor’s summary
Cognitive impairment is an unfortunately common complication of diabetes. Xu et al. investigated the underlying mechanisms in mouse models of diabetes.
In hippocampal neurons from these mice, the transcription factor Creb3 was stabilized by O-GlcNAcylation, a modification that is often enhanced by high glucose conditions, leading to greater lactate production through increased expression of the Creb3 target gene Ldha.
High amounts of lactate in the hippocampi of diabetic mice induced neuronal apoptosis and cognitive impairment.
These effects were attenuated by Ldha deficiency or by blocking the O-GlcNAcylation of Creb3 with a small peptide, suggesting that this pathway could be therapeutically targeted to preserve cognitive function in patients with diabetes. ...
Abstract
The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation.
Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose–induced cognitive impairment, a prevalent complication of diabetes.
A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes.
High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene Ldha, which encodes the enzyme lactate dehydrogenase. As a result, lactate production was increased during glycolysis, triggering neuronal apoptosis and cognitive dysfunction in mouse models of type 1 and 2 diabetes.
Expression of a Creb3 mutant that could not be O-GlcNAcylated at Ser325 or competitive blockade of the O-GlcNAcylation of Ser325 in Creb3 with a short peptide alleviated these effects.
This study elucidates a mechanistic link between high glucose–induced Creb3 O-GlcNAcylation and Ldha-mediated lactate production, offering a potential therapeutic strategy for managing diabetes-related cognitive dysfunction."
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