A positive feedback inhibition of isocitrate dehydrogenase 3ß on paired-box gene 6 promotes Alzheimer-like pathology.
Signal Transduct Target Ther
; 9(1): 105, 2024 Apr 29.
Article
in En
| MEDLINE
| ID: mdl-38679634
ABSTRACT
Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3ß (IDH3ß) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3ß induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3ß, the elevated PAX6 in turn inhibited the expression of IDH3ß, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3ß and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3ß-lactate-PAX6-IDH3ß. Breaking this loop by upregulating IDH3ß or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alzheimer Disease
/
PAX6 Transcription Factor
/
Isocitrate Dehydrogenase
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Signal Transduct Target Ther
Year:
2024
Document type:
Article
Affiliation country:
China