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 language | English |
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Pages (from-to) | 13-24 |
Journal | Neurochemistry International |
Volume | 92 |
DOIs | |
Publication status | Published - 2016 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Alzheimer's disease
- dementia
- energy metabolism
- GABA shunt
- GHB
- hypoxia