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

Antero Salminen (Corresponding Author), Paula Jouhten, Timo Sarajärvi, Annakaisa Haapasalo, Mikko Hiltunen

Research output: Contribution to journalArticleScientificpeer-review

13 Citations (Scopus)

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 ?-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 ?-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.
Original languageEnglish
Pages (from-to)13-24
JournalNeurochemistry International
Volume92
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

Fingerprint

gamma-Aminobutyric Acid
Alzheimer Disease
Citric Acid Cycle
Succinate-Semialdehyde Dehydrogenase
Cerebral Amyloid Angiopathy
Hydroxybutyrates
Aminobutyrates
Brain
Succinic Acid
Hypoxia
2,4-dihydroxybutyrate
Enzymes
Serum
Cognitive Dysfunction
succinic semialdehyde

Keywords

  • Alzheimer's disease
  • dementia
  • energy metabolism
  • GABA shunt
  • GHB
  • hypoxia

Cite this

Salminen, Antero ; Jouhten, Paula ; Sarajärvi, Timo ; Haapasalo, Annakaisa ; Hiltunen, Mikko. / Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease. In: Neurochemistry International. 2016 ; Vol. 92. pp. 13-24.
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Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease. / Salminen, Antero (Corresponding Author); Jouhten, Paula; Sarajärvi, Timo; Haapasalo, Annakaisa; Hiltunen, Mikko.

In: Neurochemistry International, Vol. 92, 2016, p. 13-24.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease

AU - Salminen, Antero

AU - Jouhten, Paula

AU - Sarajärvi, Timo

AU - Haapasalo, Annakaisa

AU - Hiltunen, Mikko

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N2 - 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 ?-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 ?-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.

AB - 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 ?-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 ?-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.

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