Hair follicles undergo repetitive stages of cell proliferation and programmed cell death. The catagen stage of physiological apoptosis is connected with dynamic changes in morphology and alterations in gene expression. However, hair follicle apoptosis must be in balance with events in surrounding tissues, such as keratinocyte cornification, to maintain complex skin homeostasis. Several pro- and anti-apoptotic molecules in the skin have been reported but mainly in pathological states. In this investigation, apoptosis-related gene expression was examined during the first catagen stage of mouse hair follicle development by PCR arrays under physiological conditions. Postnatal stages P15 and P17, representing early and late catagen stages, were evaluated relatively to stage P6, representing the hair follicle growing phase, to demonstrate dynamics of gene activation during the catagen. Several statistically significant alterations were observed at P15 and particularly at P17. Bnip3L and caspase-12 identified by the PCR arrays at both catagen stages were additionally localized using immunofluorescence and were reported in physiological hair development for the first time.

• MeSH
• Apoptosis physiology   MeSH
• Caspase 12 biosynthesis   MeSH
• Skin cytology   metabolism   MeSH
• Membrane Proteins biosynthesis   MeSH
• Mitochondrial Proteins biosynthesis   MeSH
• Mice MeSH
• Gene Expression Regulation physiology   MeSH
• Hair Follicle cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

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.

• MeSH
• Alzheimer Disease * cerebrospinal fluid   blood   diagnosis   MeSH
• Biomarkers * cerebrospinal fluid   blood   metabolism   MeSH
• Cognitive Dysfunction cerebrospinal fluid   blood   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins cerebrospinal fluid   metabolism   blood   MeSH
• Mitophagy * MeSH
• Brain metabolism   pathology   MeSH
• Tumor Suppressor Proteins MeSH
• Protein Kinases metabolism   MeSH
• tau Proteins cerebrospinal fluid   metabolism   MeSH
• Proto-Oncogene Proteins cerebrospinal fluid   blood   metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.

• MeSH
• Alzheimer Disease * blood   pathology   cerebrospinal fluid   MeSH
• Autophagy * physiology   MeSH
• Biomarkers * cerebrospinal fluid   blood   MeSH
• Frontotemporal Lobar Degeneration * pathology   cerebrospinal fluid   blood   MeSH
• Autophagy-Related Protein-1 Homolog metabolism   MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Middle Aged MeSH
• Humans MeSH
• Mitophagy * MeSH
• Protein Kinases metabolism   blood   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH