Article

Lack of Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease after Overexpression of the Anti-Apoptotic Protein Bcl-2

Department of Biology, Boise State University, Boise, Idaho 83725, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2008; 28(12):3051-9. DOI: 10.1523/JNEUROSCI.5620-07.2008
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is characterized by the accumulation of plaques containing beta-amyloid (Abeta) and neurofibrillary tangles (NFTs) consisting of modified tau. Although Abeta deposition is thought to precede the formation of NFTs in AD, the molecular steps connecting these two pathologies is not known. Previous studies have suggested that caspase activation plays an important role in promoting the pathology associated with AD. To further understand the contribution of caspases in disease progression, a triple transgenic Alzheimer's mouse model overexpressing the anti-apoptotic protein Bcl-2 was generated. Here we show that overexpression of Bcl-2 limited caspase-9 activation and reduced the caspase cleavage of tau. Moreover, overexpression of Bcl-2 attenuated the processing of APP (amyloid precursor protein) and tau and reduced the number of NFTs and extracellular deposits of Abeta associated with these animals. In addition, overexpression of Bcl-2 in 3xTg-AD mice improved place recognition memory. These findings suggest that the activation of apoptotic pathways may be an early event in AD and contributes to the pathological processes that promote the disease mechanisms underlying AD.

Download full-text

Full-text

Available from: Troy Rohn, Dec 17, 2013
0 Followers
 · 
109 Views
 · 
42 Downloads
  • Source
    • "Also, STZ-induced learning and memory dysfunction is considerably associated with oxidative stress in animal models.78,79,80 The levels of molecular markers for DNA (particularly 8-OHdG) are reported to be elevated in the brains of patients with AD.72 Bcl2 is neuroprotective against apoptotic cell death caused by Aβ.81 Accordingly, overexpression of Bcl2 could attenuate the processing of amyloid precursor protein and tau and reduce extracellular deposits of Aβ.82 Bcl2 protects neuronal cells by inhibiting the activation of caspase-3.81,82 Previously, Bcl-2 expression was shown to be upregulated, while Bax and caspase-3 were down regulated in AD models.83 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 μL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group. Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.
    Yonsei medical journal 05/2014; 55(3):689-99. DOI:10.3349/ymj.2014.55.3.689 · 1.26 Impact Factor
  • Source
    • "Considerable evidence suggests that toxicity induced by both endogenous A␤ and extracellularly applied A␤ is mediated, at least in part, via the intrinsic, mitochondria-dependent apoptotic pathway (Harada and Sugimoto, 1999; Cardoso et al., 2001; Casley et al., 2002b; Caspersen et al., 2005; Hansson Petersen et al., 2008; Cho et al., 2009; Takuma et al., 2009). Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic ⌬tau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010). Because the intrinsic apoptotic pathway may involve mitochondrial RS generation (Kirkland et al., 2001), we hypothesized that the decrease in oxidative stress caused by MitoQ treatment may prevent aberrant caspase activity in the 3xTg-AD model (Rohn et al., 2008). "
    Dataset: Jneuro11
  • Source
    • "Considerable evidence suggests that toxicity induced by both endogenous A␤ and extracellularly applied A␤ is mediated, at least in part, via the intrinsic, mitochondria-dependent apoptotic pathway (Harada and Sugimoto, 1999; Cardoso et al., 2001; Casley et al., 2002b; Caspersen et al., 2005; Hansson Petersen et al., 2008; Cho et al., 2009; Takuma et al., 2009). Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic ⌬tau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010). Because the intrinsic apoptotic pathway may involve mitochondrial RS generation (Kirkland et al., 2001), we hypothesized that the decrease in oxidative stress caused by MitoQ treatment may prevent aberrant caspase activity in the 3xTg-AD model (Rohn et al., 2008). "
Show more