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Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence.
J Alzheimers Dis. 2012; 29(4):827-40.JA

Abstract

Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.

Authors+Show Affiliations

Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. kindyms@musc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22337825

Citation

Kindy, Mark S., et al. "Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic ALZHeimer's Disease Mouse Model Expressing AβPP Containing the Wild-type Β-secretase Site Sequence." Journal of Alzheimer's Disease : JAD, vol. 29, no. 4, 2012, pp. 827-40.
Kindy MS, Yu J, Zhu H, et al. Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. J Alzheimers Dis. 2012;29(4):827-40.
Kindy, M. S., Yu, J., Zhu, H., El-Amouri, S. S., Hook, V., & Hook, G. R. (2012). Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. Journal of Alzheimer's Disease : JAD, 29(4), 827-40. https://doi.org/10.3233/JAD-2012-111604
Kindy MS, et al. Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic ALZHeimer's Disease Mouse Model Expressing AβPP Containing the Wild-type Β-secretase Site Sequence. J Alzheimers Dis. 2012;29(4):827-40. PubMed PMID: 22337825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. AU - Kindy,Mark S, AU - Yu,Jin, AU - Zhu,Hong, AU - El-Amouri,Salim S, AU - Hook,Vivian, AU - Hook,Gregory R, PY - 2012/2/17/entrez PY - 2012/2/18/pubmed PY - 2012/8/18/medline SP - 827 EP - 40 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 29 IS - 4 N2 - Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/22337825/Deletion_of_the_cathepsin_B_gene_improves_memory_deficits_in_a_transgenic_ALZHeimer's_disease_mouse_model_expressing_AβPP_containing_the_wild_type_β_secretase_site_sequence_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-2012-111604 DB - PRIME DP - Unbound Medicine ER -