Cathepsin D overexpression in the nervous system rescues lethality and Ab42 accumulation of cathepsin D systemic knockout in vivo

January 1, 2023
Acta Pharm Sin B
https://pubmed.ncbi.nlm.nih.gov/37799377

This article is currently being updated. View its version on PubMed.

https://pubmed.ncbi.nlm.nih.gov/37799377

Research summary

This study investigates the role of Cathepsin D (CTSD), a lysosomal protease, in neurodegeneration and amyloid-beta (Aβ) accumulation. Researchers generated a mouse model with overexpression of human CTSD specifically in the nervous system to assess its effects on lifespan, proteasomal function, and Aβ42 accumulation in systemic CTSD Knockout mice.

Key outcome of the study

Overexpression of CTSD in the nervous system extended the lifespan of systemic CTSD Knockout mice, partially rescued proteasomal deficits, and reduced the accumulation of Aβ42. These findings suggest that CTSD plays a crucial role in maintaining proteostasis and preventing neurodegeneration associated with lysosomal dysfunction.

Mouse model

The study utilized a transgenic mouse model where human CTSD cDNA was inserted into the Hprt locus with a floxed STOP cassette under the control of the ubiquitous CAG promoter. Crossing these mice with Nestin-Cre mice allowed for nervous system-specific overexpression of CTSD upon Cre-mediated recombination.

TARGET:
Ctsd
Cathepsin D

Keywords

Neurodegeneration, Lysosomal storage disorders, Amyloid-beta, Proteostasis, Cathepsin D

Technical specifications

Transgenic mouse model, Nervous system-specific overexpression, Cre-loxP system, Lysosomal protease, Neurodegenerative disease model

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