**8. Conclusion**

The brain as well as the BBB have complex structural and functional physiology which demands a continuous supply of high energy. Bioenergetic pathways in the brain utilize multiple pathways (such as glycolytic metabolism, TCA cycle etc) to ensure that the energy requirements of the different cell types in the brain are fulfilled at all time. The BBB acts as a critical interface to buffer and influx energy substrates into the brain. Shuttling of multiple substrates such as glucose, lactose as well as glycogen derived lactate/glucose commonly occurs between the neurons and the astrocytes. Various DHOs are a critical part of these bioenergetic pathways and occurrence of DHO defect can lead to inborn errors in the metabolism followed by strong neurological complications. PDH is an imporant IEM which is directly linked to bioenergectic pathways such as TCA cycle and aerobic respiration. Apart from energy metabolism, BCKDH and SSD are IEMs that correlate to other pathways in the brain such as amino acid metabolism and neurotransmitter degradation. DHOs (such as ALDHs) also play an important role to further degrade the biogenic aldehydes derived from the degradation pathways of neurotransmitters such as for epinephrine, norepinephrine and GABA which are commonly synthesized in the brain. Furthermore, DHOs play an important role in oxidation of fatty acids as an energy supply. Although this does not occur in the brain, IEMs affecting these dehydrogenases have shown to correlate with at least one reported neurological complication (such as Reye-like syndrome).

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Aging naturally promotes alterations and/or reduction in DHOs' activity which can alter mitochondrial functions leading to hypometabolism other metabolic dysfunction. This can ultimately facilitate the onset and progression of various neurological disorders such as Alzheimer's disease and PD. Specifically, altered expression/function of ABAD and ALDH2 have been associated with the pathogenesis of Alzheimer's disease whereas alteration of ALDH1A1, ALDH2, GDH2 and ABAD have been linked to PD.

In summary, DHOs play a critical role in supporting neuronal and BBB functions. They constitute an integral part of various metabolic pathways in the brain associated with energy metabolism, as well as synthesis and degradation of neurotransmitters. Their optimal functioning facilitates neuronal signaling and homeostasis. In born as well as acquired defects in DHOs have been shown to correlate with various CNS and BBB pathophysiologies.
