Mitophagy biomarkers are changed in the continuum of Alzheimer’s disease

Abstract

AbstractBackgroundAutophagy is a cellular self “garbage clearance ”system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer’s disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU).MethodWe included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 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), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation).ResultWe found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps<.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps<.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng.ConclusionWe identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade.