Dataset Information

Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing A?PP containing the wild-type ?-secretase site sequence.

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 ?-secretase which, in most AD patients, cleaves the wild-type (WT) ?-secretase site sequence of the amyloid-? protein precursor (A?PP) to produce neurotoxic amyloid-? (A?). Thus, an animal model representing most AD patients for evaluating ?-secretase effects on memory deficits is one that expresses human A?PP containing the WT ?-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have ?-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 A?PP containing the WT ?-secretase site sequence and the London ?-secretase site (A?PPWT/Lon mice). Knockout of the CatB gene in the A?PPWT/Lon mice improved memory deficits and altered the pattern of A?-related biomarkers in a manner consistent with CatB having WT ?-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the A?PPWT/Lon mice. These data are the first to show that knockout of a putative ?-secretase gene results in improved memory in an AD animal model expressing the WT ?-secretase site sequence of A?PP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.

SUBMITTER: Kindy MS

PROVIDER: S-EPMC4309289 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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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.

Kindy Mark S MS Yu Jin J Zhu Hong H El-Amouri Salim S SS Hook Vivian V Hook Gregory R GR

Journal of Alzheimer's disease : JAD 20120101 4

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 on ...[more]

PMID: 22337825

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Project description:BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

Project description:IntroductionCell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.MethodsIn this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an A?PP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid ?-peptides (A?) deposition, and microglial function of the mice were investigated.ResultsWe found that transplantation of HUMSC-NCs into A?PP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced A? deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?), was significantly reduced. Moreover, the expression of A?-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.ConclusionsHUMSC-NC transplantation decreased A? deposition and improved memory in A?PP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.

Dataset Information

Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing A?PP containing the wild-type ?-secretase site sequence.

Publications

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.

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