Objective: To study the involvement of cathepsin D in the pathogenesis of Tau-related conditions.

Background: The endo-lysosomal system (ELS) is central in processing of neurodegenerative disease related proteins and therefore a major player in the pathogenesis. Since therapies targeting the ELS are on the rise, it is important to understand distinct patterns of the ELS response. Morphological and genetic studies highlighted the relation of Amyloid-beta (Ab), prion protein (PrP), TDP-43, alpha-synuclein and the ELS, including cathepsin D, a major lysosomal proteolytic enzyme. However, there is a paucity of data on the subcellular mechanisms of the processing of tau and whether there are differences between conditions.

Method: A five-step approach was used: 1) Using a neuron-specific morphometric approach, we examined the expression of the lysosomal cathepsins D in the frontal cortex in high-level Alzheimer’s disease related neuropathologic change (ADNC), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP); 2) We quantified the co-localization of cathepsin D and p-Tau and; 3) We performed immunogold electron microscopy to evaluate whether p-Tau is deposited in lysosomes; 4) We compared single nuclear RNAseq of PSP and non-diseased brains to compare Cathepsin D expression; and 5) We treated Tau RD P301S FRET Biosensor cells with tau filaments derived from AD and CBD brains and performed Cathepsin D activity assay following treatment with a Cathepsin D inhibitor and an enhancer.

Results: We observed distinct morphological and co-localization patterns of cathepsin D immunoreactivity with p-Tau in different tau cytopathologies in the disease studied. While Cathepsin D did not colocalize with p-Tau in AD, supported also by ultrastructural observations, in CBD we found significant colocalization. We found cell-specific differences of cathepsin D RNA expression in PSP. Finally, our cell culture experiments showed that inhibiting cathepsin D with pepstatin A increase tau seeding.

Conclusion: Our results indicate a differential response of the ELS to tau accumulation in disease with distinct folds of tau filaments. Moreover, we recognized overlapping and distinct aspects of ELS involvement when comparing tau with PrP, alpha-synuclein, TDP-43, and Ab. Our study informs therapy developers on the complexity of the contribution of ELS in the pathogenesis to pave the path towards disease-specific treatments targeting the ELS.

References: 1: Kovacs GG, et al. Involvement of the endosomal-lysosomal system correlates with regional pathology in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol. 2007 Jul;66(7):628-36.
2: Puska G, et al. Lysosomal response in relation to α-synuclein pathology differs between Parkinson’s disease and multiple system atrophy. Neurobiol Dis. 2018 Jun;114:140-152.
3: Matej R, et al. Increased neuronal Rab5 immunoreactive endosomes do not colocalize with TDP-43 in motor neuron disease. Exp Neurol. 2010 Sep;225(1):133-9

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/is-cathepsin-d-a-good-target-for-therapy-in-tau-related-conditions/