title: 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.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. Electronic address: antero.salminen@uef.fi.
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.affiliation: VTT Technical Research Centre of Finland, FIN-00014 Helsinki, Finland; EMBL European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Jouhten
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, Neulaniementie 2, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland; Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002072:Butylene Glycols / Q000378:metabolism; D002087:Butyrates / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D012978:Sodium Oxybate / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002072:Butylene Glycols; D002087:Butyrates; C021996:2,4-dihydroxybutyrate; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate
keywords: Alzheimer's disease; Dementia; Energy metabolism; GABA shunt; GHB; Hypoxia