Genetic cathepsin B deficiency reduces β-amyloid in transgenic mice expressing human wild-type amyloid precursor protein

Depts of Neurosciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0744, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2009; 386(2):284-8. DOI: 10.1016/j.bbrc.2009.05.131
Source: PubMed


Neurotoxic beta-amyloid (Abeta) peptides participate in Alzheimer's disease (AD); therefore, reduction of Abeta generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human Abeta may identify targets for reducing Abeta. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decreases in brain Abeta40 and Abeta42 by 67% and decreases in levels of the C-terminal beta-secretase fragment (CTFbeta) derived from APP. In contrast, knockout of cathepsin B in mice expressing hAPP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Abeta. The difference in reduction of Abeta in hAPPwt mice, but not in hAPPSwe/Ind mice, shows that the transgenic model can affect cathepsin B gene knockout results. Since most AD patients express hAPPwt, these data validate cathepsin B as a target for development of inhibitors to lower Abeta in AD.

Download full-text


Available from: Greg Hook
  • Source
    • "Kif1a is a member of the kinesin family (KIFs) (Takemura et al., 1996) and has previously been connected to AD (Kondo et al., 2012). These microtubule-based motor proteins transport membrane organelles, mRNA, and proteins (Hirokawa et al., 2009). By transporting those complexes, KIFs play important roles in neuronal function and plasticity as well as morphogenesis and survival (Hirokawa et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.
    Full-text · Article · Apr 2014 · Frontiers in Aging Neuroscience
  • Source
    • "In addition, the activation of c-fos expression in neurons following TLT suggests that increased neuronal activity may provide a mechanism to protect the cells from damage as well as reduce the production of A␤ peptide . The reduction in A␤ peptide levels could be the result of alterations in BACE1 or cathepsin B activity as suggested by the changes in sA␤PP␣ and CTF␤ levels in the brain of TLT treated animals (Fig. 6) [22] [38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcranial near-infrared laser therapy (TLT) improves stroke outcome in animal models. Adequate laser doses are necessary to exert therapeutic effects. However, applying higher laser energy may cause cortical tissue heating and exacerbate stroke injury. The objective of this study is to examine the thermal effect and safety of transcranial near-infrared laser therapy. Diode laser with a wavelength of 808nm was used to deliver different power densities to the brain cortex of rabbits. Cortical temperature was monitored and measured using a thermal probe during the 2min transcranial laser irradiation. Neuro-pathological changes were examined with histological staining 24hrs after laser treatment. Transcranial laser irradiation for 2min at cortical power densities of 22.2 and 55.6 mW/cm(2) with continuous wave (CW) did not increase cortical temperature in rabbits. With the same treatment regime, cortical power density at 111.1 mW/cm(2) increased brain temperature gradually by 0.5°C over the 2min exposure and returned to baseline values within 1-2min post-irradiation. Separately, histological staining was evaluated after triple laser exposure of 22.2 mW/cm(2) CW and 111.1 mW/cm(2) pulse wave (PW) and showed normal neural cell morphology. The present study demonstrated that the TLT powers currently utilized in animal stroke studies do not cause cortical tissue heating and histopathological damage.
    Full-text · Article · Aug 2013 · Neuroscience Letters
  • Source
    • "A similar analysis could also explain apparent conflicting BACE1 knockout data. Others have reported that deleting the BACE1 gene caused a decrease in flAβ in PDGF-AβPP [88] or AβPP51/16 mice [89], which express AβPP-751/770 and AβPP-751, respectively, containing the wt β-secretase site sequence, whereas we show here and previously that the BACE1 gene deletion in AβPPLon mice expressing AβPP-695 had no effect on flAβ [49] [50]. Clearly, there are differences in PDGF-AβPP and AβPP51/16 mouse models expressing AβPP-751/770 [88] [89] compared to our study here of AβPPLon mice expressing AβPP-695, the major isoform of AβPP expressed in human brain [44] [45] [46] [47] [48]. "

    Full-text · Article · Jul 2013 · Alzheimer's and Dementia
Show more