Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease.

Abstract

We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis.

• Authors: Antero Salminen, Paula Jouhten, Timo Sarajärvi, Annakaisa Haapasalo, Mikko Hiltunen
• Journal: Neurochemistry international (Neurochem Int) Vol. 92 Pg. 13-24 (Jan 2016) ISSN: 1872-9754 [Electronic] England
• PMID: 26617286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Butylene Glycols
• Butyrates
• 2,4-dihydroxybutyrate
• gamma-Aminobutyric Acid
• Sodium Oxybate

Topics

• Alzheimer Disease (metabolism, pathology)
• Animals
• Butylene Glycols (metabolism)
• Butyrates (metabolism)
• Humans
• Hypoxia (pathology)
• Sodium Oxybate (metabolism)
• gamma-Aminobutyric Acid (metabolism)