Mice lacking both cathepsin B and L, two lysosomal proteases that have been implicated in the development of Alzheimer's disease, suffer a profound loss of neurons soon after birth, Ute Felbor and colleagues at Harvard Medical School and elsewhere report in the June 11 PNAS, now available online. Earlier knockout mouse strains missing only one of these two cysteine proteases showed few symptoms, suggesting that cathepsin B and L compensate for each other. Taking out both, however, caused unprecedented brain atrophy, the authors write. "The phenotype of these mice was a surprise to us and very dramatic," senior author Bjorn Olsen said. The study ties into ongoing research on whether age-related changes in cathepsin activity play a role in AD, or in neurodegeneration generally.
Felbor et al. crossed mice lacking cathepsin B with another strain lacking cathepsin L. Among the offspring, only those missing all four cathepsin alleles showed the described phenotype. They stopped growing soon after birth and died emaciated after about two weeks. Those reared without competition from healthy littermates survived to around day 50, allowing for more extensive analysis of postnatal development. Curiously, even though cathepsin B and L are expressed in most organs, only the brain was severely affected. The cerebral cortex and cerebellum showed pronounced atrophy and massive apoptosis. Astrogliosis accompanied this neurodegeneration, as seen in humans. Degenerating neurons contained membranous inclusions around their nuclei and in their axons that looked like remnants of lysosomes in the electron microscope.
The relevance of this paper for AD research is unclear. Previous work has implicated cathepsin proteases in AD or, more broadly, in age-related neurodegeneration. Yet clearly delineating the in-vivo function for these enzymes is difficult because their substrate specificities overlap. For example, cathepsins D and E have been implicated in AβPP processing (Gruninger-Leitch et al, 2000), and cathepsin B released from activated microglia is reported to induce apoptosis in neurons (Kingham & Pocock, 2001). Cathepsin B and L inhibitors infused into brain ventricles or applied to cultured brain slices cause age-related changes (Yong et al, 1999), and when applied to hippocampal slices from ApoE-knockout mice they cause AD-like neurofibrillary tangles, suggesting lysosomal dysfunction plays a role in the development of AD (Bi et al., 2001). On the genetic front, earlier studies reporting links between various cathepsin polymorphisms and increased AD risk have not been widely replicated (Bertram et al., 2000; Bhojak et al., 2001).—Gabrielle Strobel
- Bi X, Yong AP, Zhou J, Ribak CE, Lynch G. Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8832-7. PubMed.
No Available Further Reading
- Felbor U, Kessler B, Mothes W, Goebel HH, Ploegh HL, Bronson RT, Olsen BR. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7883-8. PubMed.