Cortical neurons transgenic for human Abeta40 or Abeta42 have similar vulnerability to apoptosis despite their different amyloidogenic properties

Department of Physiology, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA. ,
International journal of clinical and experimental pathology (Impact Factor: 1.89). 02/2009; 2(4):339-52.
Source: PubMed


Alzheimer's disease (AD) is a leading cause of chronic dementia in the United States. Its incidence is increasing with an attendant increase in associated health care costs. Amyloid beta peptide (Abeta; a 39-42 amino acid molecule) is the major component of senile plaques, the hallmark lesion of AD. The toxic mechanism of Abeta peptides has not been well characterized. Specifically, the impact of Abeta1-40 (Abeta40) and its slightly longer counterpart fragment, Abeta1-42 (Abeta42), is not clearly understood. It has been suggested that, while Abeta40 might play a more physiologically relevant role, Abeta42 is likely the key amyloidogenic fragment leading to amyloid deposition in the form of plaques in AD, a pivotal process in Alzheimer's pathology. This notion was further supported by a recent study employing transgenic mouse models that expressed either Abeta40 or Abeta42 in the absence of human amyloid beta protein precursor (APP) overexpression. It was found that mice expressing Abeta42, but not Abeta40, developed compact amyloid plaques, congophilic amyloid angiopathy, and diffuse Abeta deposits. Since neuronal loss is one of the hallmark features in AD pathology, we hypothesize that cortical neurons from these two strains of transgenic mice for Abeta might show different vulnerability to cell death induced by classical inducers of apoptosis, such as trophic factor withdrawal (TFW). Contrary to our expectations, we found that, while overexpression of either Abeta40 or 42 significantly increased the vulnerability of primary cortical neurons to WFT-induced cell death, there was no significant difference between the two transgenic lines. Mitochondrial dysfunction, levels of oxidative stress, caspase activation and nuclear fragmentation are increased to about the same extent by both Abeta species in transgenic neurons. We conclude that Abeta40 or Abeta42 induce similar levels of neurotoxicity following TFW in these transgenic mice despite the difference in their amyloidogenic properties.

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    • "This report represents research that is a mechanistic extension to previously reported findings from our laboratory [30]. In the previous work we found that overexpression of Aβ40 and Aβ42 almost equally increased neuronal susceptibility to oxidative stress, mitochondrial dysfunction and apoptotic cell death when the cellular environment becomes hostile under nutritive stress induced by TFW, which simulates the conditions of an aged Alzheimer's brain. "
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    ABSTRACT: The pathogenesis of Alzheimer's Disease (AD) is not fully understood. Amyloid plaques could be causally linked to neuronal loss in AD. Two proteolytic products of the Amyloid Precursor Protein (APP), Amyloid beta40 (Abeta40) and Amyloid beta42 (Abeta42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Abeta40 or Abeta42, it was shown that Abeta42 was much more amyloidogenic than Abeta40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Abeta40 and for Abeta42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP(3)R (Inositol triphosphate receptor)-mediated calcium release has been implicated in neuronal cell death. It is however not clear whether this pathway plays a critical role in cortical neurons transgenic for different species of human Abeta. We now report that Abeta40 and Abeta42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP(3)R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in [Ca(2+)](i) but this was not observed in either Abeta transgenic type. Similarly, when 1 muM Xestopongin C (XeC), a specific blocker of InsP(3)R, was applied to these neurons, WT cells showed a significant attenuation of increase in [Ca(2+)](i) following TFW, while elevation in [Ca(2+)](i) induced by TFW remained largely unchanged in Abeta40 and Abeta42 cells. Finally, when we treated these cells with a Ca(2+) chelator (BAPTA; 10 muM), all three cell types had a marked attenuation of [Ca(2+)](i). These findings indicate that the exacerbated calcium dysregulation following TFW in Abeta transgenic neurons are likely to be mediated by calcium channels other than ER InsP3R receptors. Overall, our results also suggest that a highly amyloidogenic Abeta species, such as Abeta42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Abeta40.
    International Journal of Clinical and Experimental Medicine 02/2009; 2(2):149-58. · 1.28 Impact Factor
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    ABSTRACT: Improvement in cognitive scores in patients with Alzheimer's disease (AD) has been reported in two trials in which intravenous immunoglobulin (IvIg) preparations were administered. IvIg's benefits in AD patients have been suggested to be due to antibodies to amyloid-beta (Abeta). Our previous study using indirect enzyme-linked immunosorbent assay (ELISA) indicated that much of IvIg's apparent binding to Abeta1-42 is nonspecific; it is detectable even when IvIg is incubated on "specificity controls" (bovine serum albumin [BSA] and Abeta reverse sequence Abeta42-1) rather than Abeta1-42. The objective of this study was to evaluate procedures that might reduce this nonspecific binding. The IvIg preparation used was Gamunex (Talecris Biotherapeutics). Multiple blocking agents were evaluated, but even the most effective blocker only reduced nonspecific binding by 48%. Dissociating Gamunex's antibody-antigen complexes had no effect on specific binding when Abeta42-1 was used as the specificity control, although it increased this binding when BSA was the specificity control. Decreasing Gamunex's dilution from 1:1,500 to 1:500 resulted in a slight (7.4%) but significant (p=0.027) increase in specific binding. Using a sandwich ELISA to measure Gamunex's anti-Abeta antibodies resulted in even less specific binding to Abeta1-42 than with the indirect ELISA. Despite Gamunex's low percentage of specific binding to Abeta1-42, it inhibited Abeta oligomer formation. We conclude that, when anti-Abeta antibodies in IvIg are measured by indirect ELISA, extensive nonspecific binding occurs despite procedures taken to prevent it. This must be subtracted from total binding to accurately measure specific anti-Abeta antibody concentrations.
    Journal of Neuroscience Methods 03/2010; 187(2):263-9. DOI:10.1016/j.jneumeth.2010.01.018 · 2.05 Impact Factor
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    ABSTRACT: Neuropathological hallmarks of Alzheimer's disease (AD) include amyloid plaque formation, neurofibrillary tangles, neuronal and synaptic loss. This study aims to identify the neuroprotective effects of the selenium compounds on the neurotoxicity of amyloid β(1-42) in primary cultures of murine hippocampal neurons. Samples were subjected to immunocytochemistry and western blotting techniques to determine the role of treatments on neuronal viability and synaptic protein SNAP-25. We observed a reduced cell viability amyloid β-peptide (1-42)-induced. When cells were co-treated with amyloid β-peptide (1-42) and selenium compounds, we verified a strong increase in relative cell viability and in the level of synaptic marker synaptosomal-associated protein SNAP-25 induced by selenium compounds.
    Neurochemical Research 09/2013; 38(11). DOI:10.1007/s11064-013-1147-4 · 2.59 Impact Factor
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