Abstract
AbstractBackgroundReduced removal of dysfunctional mitochondria has been implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer’s disease (AD) and Frontotemporal lobar degeneration (FTLD). Mitophagy is the main cellular pathway through which aberrant and aged mitochondria are removed. Impaired neuronal mitophagy triggers the accumulation of damaged mitochondria, leading to cell death and neurodegeneration. While recent evidence suggests that levels of various mitophagy‐associated proteins are altered in AD, whether and in which direction mitophagy biomarkers are altered in non‐AD pathologies remains unclear. Therefore, we aimed to compare the levels of mitophagy markers between biomarker‐defined patients in various stages of AD and FTLD and cognitively unimpaired individuals (CU).MethodWe included 253 biomarker‐defined individuals from Czech Brain Aging Study: 86 AD dementia (ADD), 86 mild cognitive impairment due to AD (AD‐MCI) 21 FTLD dementia (FTLDD), 21 MCI due to FTLD (FTLD‐MCI), and 39 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), and mitophagy biomarkers in CSF (ULK1‐ autophagy factor essential for mitophagy initiation) and in serum (TFEB‐ transcription factor critical for mitophagic flux).ResultWe found a significant increase in ULK1 CSF levels in MCI‐FTLD compared to MCI‐AD (p<.01), ADD (p<.001), and CU (p<.01). There was also a significant increase in TFEB serum levels in FTLDD compared to MCI‐AD (p<.01) and CU (p<.01). Similarly, TFEB serum levels were elevated in FTLD‐MCI compared to ADD (p<.001), but were not elevated compared to CU.ConclusionThere is an upregulation in the key mitophagy activator (ULK1) and in the mitochondrial quality control protein (TFEB) in FTLD compared to AD in various stages of disease (MCI vs dementia). Our data suggest that mitophagy plays different roles in the sub‐types of neurocognitive disorders, with a significant increase in the levels of mitophagy markers in patients with FTLD compared to healthy controls and patients with AD. Further research is needed to elucidate the role of mitophagy in the pathophysiology of different sub‐types of neurocognitive disorders.
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