Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease

• Published in: Autophagy Vol. 20; no. 8; pp. 1868 - 1878
• Main Authors: Veverová, Kateřina, Laczó, Jan, Katonová, Alžběta, Horáková, Hana, Matušková, Veronika, Angelucci, Francesco, Laczó, Martina, Nedelská, Zuzana, Hort, Jakub, Wang, He-Ling, Zhang, Jianying, Shi, Liu, Fei Fang, Evandro, Vyhnálek, Martin
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02-08-2024
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - blood; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnosis; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biomarkers - blood; Biomarkers - cerebrospinal fluid; Biomarkers - metabolism; BNIP3L; Brain - metabolism; Brain - pathology; Clinical Research Paper; Cognitive Dysfunction - blood; Cognitive Dysfunction - cerebrospinal fluid; Cognitive Dysfunction - diagnosis; Female; Humans; Male; Membrane Proteins - blood; Membrane Proteins - cerebrospinal fluid; Membrane Proteins - metabolism; Middle Aged; mild cognitive impairment; Mitophagy; PINK1; Protein Kinases - metabolism; Proto-Oncogene Proteins - blood; Proto-Oncogene Proteins - cerebrospinal fluid; Proto-Oncogene Proteins - metabolism; tau Proteins - cerebrospinal fluid; tau Proteins - metabolism; TFEB; Tumor Suppressor Proteins; TFEB; BNIP3L; PINK1; mitophagy; mild cognitive impairment; Autophagy
• ISSN: 1554-8627; 1554-8635; 1554-8635
• DOI: 10.1080/15548627.2024.2340408

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.
Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.