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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: 2.24). 02/2009; 2(4):339-52.
Source: PubMed

ABSTRACT 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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    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.
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    [show abstract] [hide abstract]
    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 β40 (Aβ40) and Amyloid β42 (Aβ42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Aβ40 or Aβ42, it was shown that Aβ42 was much more amyloidogenic than Aβ40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Aβ40 and for Aβ42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP3R (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 Aβ. We now report that Aβ40 and Aβ42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP3R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in (Ca2+)i but this was not observed in either Aβ transgenic type. Similarly, when 1 μM Xestopongin C (XeC), a specific blocker of InsP3R, was applied to these neurons, WT cells showed a significant attenuation of increase in (Ca2+)i following TFW, while elevation in (Ca2+)i induced by TFW remained largely unchanged in Aβ40 and Aβ42 cells. Finally, when we treated these cells with a Ca2+ chelator (BAPTA; 10 μM), all three cell types had a marked attenuation of (Ca2+)i. These findings indicate that the exacerbated calcium dysregulation following TFW in Aβ 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 Aβ42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Aβ40.

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Najeeb A. Shiwany