Lysosomal cathepsin D is upregulated in Alzheimer's disease neocortex and may be a marker for neurofibrillary degeneration.

Abstract

Alzheimer's disease (AD) is characterized by accumulation of β-amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α-synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co-localize at least partly to NFT-containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co-localize with α-synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD-related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α-synuclein inclusions in Lewy body dementia.

• Authors: Yuek Ling Chai, Joyce R Chong, Jiaju Weng, David Howlett, Andrea Halsey, Jasinda H Lee, Johannes Attems, Dag Aarsland, Paul T Francis, Christopher P Chen, Mitchell K P Lai
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 29 Issue 1 Pg. 63-74 (01 2019) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 30051532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 International Society of Neuropathology.

Chemical References

• Amyloid beta-Peptides
• Biomarkers
• alpha-Synuclein
• tau Proteins
• CTSD protein, human
• Cathepsin D

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Biomarkers
• Cathepsin D (genetics, metabolism, physiology)
• Female
• Humans
• Lewy Bodies (pathology)
• Lewy Body Disease (pathology)
• Male
• Neocortex (metabolism, physiology)
• Neurodegenerative Diseases (physiopathology)
• Neurofibrillary Tangles (metabolism)
• Neurons (pathology)
• Parietal Lobe (pathology)
• Plaque, Amyloid (pathology)
• Temporal Lobe (pathology)
• alpha-Synuclein (metabolism)
• tau Proteins (metabolism)