Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Genetics

Background:

• Alzheimer's disease (AD) involves a vicious cycle where amyloid-beta (Aβ) causes mitochondrial dysfunction and oxidative stress, accelerating Aβ buildup.
• The precise molecular mechanisms driving this cycle and potential therapeutic interventions remain unclear.

Purpose of the Study:

• To investigate the therapeutic potential of human mitochondrial transcriptional factor A (hTFAM) in mitigating AD pathology.
• To explore hTFAM's role in protecting mitochondria from oxidative stress and its impact on Aβ accumulation and cognitive function.

Main Methods:

• Utilized a 3xTg-AD mouse model and human induced pluripotent stem cell (iPSC)-derived neurons with a PSEN1 mutation.
• Assessed the effects of hTFAM expression and recombinant hTFAM treatment on mitochondrial DNA (mtDNA) integrity, Aβ levels, oxidative stress markers (8-oxoguanine), and transthyretin expression.
• Evaluated cognitive function in the AD mouse model.

Main Results:

• hTFAM expression significantly improved cognitive function in 3xTg-AD mice.
• hTFAM reduced 8-oxoguanine in mtDNA and intracellular Aβ accumulation, while increasing transthyretin expression.
• In AD model neurons, extracellular hTFAM treatment reversed mitochondrial dysfunction, mtDNA damage, and impaired neuritogenesis, decreasing Aβ and increasing transthyretin.

Conclusions:

• hTFAM demonstrates significant neuroprotective effects against AD pathology by maintaining mitochondrial integrity and reducing oxidative stress.
• hTFAM represents a promising therapeutic target for Alzheimer's disease, potentially by restoring mitochondrial function and inhibiting Aβ aggregation.