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. 2024 Jan 17;25(2):1125.
doi: 10.3390/ijms25021125.

Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia

Antonio Longobardi  1 , Marcella Catania  2 , Andrea Geviti  3 , Erika Salvi  4   5 , Elena Rita Vecchi  2 , Sonia Bellini  1 , Claudia Saraceno  1 , Roland Nicsanu  1 , Rosanna Squitti  1   6 , Giuliano Binetti  7 , Giuseppe Di Fede  2 , Roberta Ghidoni  1
Affiliations

Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia

Antonio Longobardi et al. Int J Mol Sci. .

Abstract

The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.

Keywords: ATG5; Alzheimer’s disease; LC3; UBQLN2; ULK1; autophagy; brain; dementia with Lewy bodies; frontotemporal dementia; neurodegeneration.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Boxplots of ATG5, UBQLN2, ULK1, and LC3 levels in brain specimens. (a) Temporal cortex. A statistically significant decrease in ATG5 levels was observed in DLB and FTD groups compared to those in the CTRL group. UBQLN2 and ULK1 levels resulted in being significantly decreased in the DLB group compared to those in the CTRL group. LC3 was decreased in DLB and FTD specimens compared to that in AD specimens. (b) Frontal cortex. UBQLN2 levels were significantly decreased in DLB and FTD groups compared to those in the CTRL group. LC3 levels resulted in being significantly increased in the DLB and FTD groups compared to those in the CTRL group. UBQLN2 was decreased in the DLB and FTD groups compared to that in the AD group. LC3 was increased in DLB and FTD specimens compared to that in AD specimens. (c) Occipital cortex. No differences were shown between patient groups and the CTRL group in terms of ATG5, UBQLN2, ULK1, and LC3 levels. ULK1 and LC3 were decreased in the DLB group compared to those in the AD group. * padj < 0.05. Linear regression analysis corrected for age as a confounder was conducted, with Benjamini–Hochberg correction for multiple comparisons.
Figure 1
Figure 1
Boxplots of ATG5, UBQLN2, ULK1, and LC3 levels in brain specimens. (a) Temporal cortex. A statistically significant decrease in ATG5 levels was observed in DLB and FTD groups compared to those in the CTRL group. UBQLN2 and ULK1 levels resulted in being significantly decreased in the DLB group compared to those in the CTRL group. LC3 was decreased in DLB and FTD specimens compared to that in AD specimens. (b) Frontal cortex. UBQLN2 levels were significantly decreased in DLB and FTD groups compared to those in the CTRL group. LC3 levels resulted in being significantly increased in the DLB and FTD groups compared to those in the CTRL group. UBQLN2 was decreased in the DLB and FTD groups compared to that in the AD group. LC3 was increased in DLB and FTD specimens compared to that in AD specimens. (c) Occipital cortex. No differences were shown between patient groups and the CTRL group in terms of ATG5, UBQLN2, ULK1, and LC3 levels. ULK1 and LC3 were decreased in the DLB group compared to those in the AD group. * padj < 0.05. Linear regression analysis corrected for age as a confounder was conducted, with Benjamini–Hochberg correction for multiple comparisons.
Figure 2
Figure 2
Concentrations of ATG5 (a) and UBQLN2 (b) in plasma samples. Levels of ATG5 resulted in being decreased in AD, DLB, and FTD samples compared to those in CTRL samples (a). Levels of UBQLN2 resulted in being decreased in AD samples compared to those in CTRL samples, showing a downward trend in DLB and FTD samples (b). Multinomial logistic regression corrected for age and gender as confounders was performed, with Benjamini–Hochberg correction for multiple comparisons.
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