The brain is a high energy consuming tissue that needs a continuous supply of energy substrates from the circulation for optimal neurological function. Astrocytes are important for regulating the relationship between energy consumption and dynamic neuronal activity in the brain and are mainly involved in processes used for efficient transfer of energy substrates to neurons. Changes in astrocyte energy metabolism could therefore potentially disrupt essential neuronal processes, and this cell type has also been shown to undergo structural and biochemical changes in Alzheimer's disease (AD). Here the cell type distribution and cellular levels of the brain enzyme CKB, which is crucial for energy homeostasis and known to have decreased activity in AD, has been investigated to identify changes associated with neurodegenerative processes.

CKB, the brain isozyme of the creatine kinase enzyme family is part of a system known as the CK/PCr shuttle that buffers energy availability and keeps the balance between ATP generation and consumption. A decrease of CKB immunoreactivity has been found in AD brains, but it is important to further investigate the mechanisms, cell types, and biological processes associated with this activity loss to understand how astrocytes and their functions are affected in neurodegenerative diseases.

In this study CKB levels in neurons, astrocytes, oligodendrocytes, and microglia from non-demented and AD human cortex brain samples were evaluated based on IF, Western blot and MS data. The results show an association between reduced levels of CKB and AD progression that is not dependent on astrocyte cell death, reduced expression or translation, or protein-protein interactions. Instead, the MS data suggest that the decrease is a consequence of PTMs in the AD brain affecting both antibody-binding and trypsin interaction. PTMs in CKB, and astrocyte dysfunction may disrupt the CK/PCr shuttle, disrupt homeostasis and thereby lead to neuronal injury in the brain. CKB and its activity might therefore be interesting potential biomarkers for monitoring early-stage energy deficits in AD.

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