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Int J Clin Exp Pathol 2(4),339-352;2009
Original Article
Cortical Neurons Transgenic for Human Aβ40 or Aβ42 have Similar Vulnerability to
Apoptosis despite Their Different Amyloidogenic Properties
Najeeb A Shiwany, Jun Xie, and Qing Guo
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Received 23 October 2008; Accepted 26 October 2008; Available online 26 November 2008
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 β peptide (Aβ; a 39-42 amino acid molecule) is the major component of senile plaques, the
hallmark lesion of AD. The toxic mechanism of Aβ peptides has not been well characterized. Specifically, the impact of Aβ1-40 (Aβ40) and its
slightly longer counterpart fragment, Aβ1-42 (Aβ42), is not clearly understood. It has been suggested that, while Αβ40 might play a more
physiologically relevant role, Aβ42 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 Αβ40 or Αβ42 in the absence of human amyloid beta protein precursor (APP) overexpression. It was found that mice expressing Αβ42, but
not Αβ40, developed compact amyloid plaques, congophilic amyloid angiopathy, and diffuse Aβ 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 Aβ 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 Aβ40 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 Aβ species in transgenic neurons. We conclude that Αβ40
or Αβ42 induce similar levels of neurotoxicity following TFW in these transgenic mice despite the difference in their amyloidogenic properties.
(IJCEP810008).
Key Words: Alzheimer’s disease, amyloid beta-peptide, transgenic mouse model, cortical neurons, cell death, trophic factor withdrawal
Full text PDF
Address all correspondence to: Qing Guo, MD, PhD, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma
City, OK 73104, E-mail: qing-guo@ouhsc.edu; najeeb-shirwany@ouhsc.edu
Original Article
Cortical Neurons Transgenic for Human Aβ40 or Aβ42 have Similar Vulnerability to
Apoptosis despite Their Different Amyloidogenic Properties
Najeeb A Shiwany, Jun Xie, and Qing Guo
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Received 23 October 2008; Accepted 26 October 2008; Available online 26 November 2008
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 β peptide (Aβ; a 39-42 amino acid molecule) is the major component of senile plaques, the
hallmark lesion of AD. The toxic mechanism of Aβ peptides has not been well characterized. Specifically, the impact of Aβ1-40 (Aβ40) and its
slightly longer counterpart fragment, Aβ1-42 (Aβ42), is not clearly understood. It has been suggested that, while Αβ40 might play a more
physiologically relevant role, Aβ42 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 Αβ40 or Αβ42 in the absence of human amyloid beta protein precursor (APP) overexpression. It was found that mice expressing Αβ42, but
not Αβ40, developed compact amyloid plaques, congophilic amyloid angiopathy, and diffuse Aβ 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 Aβ 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 Aβ40 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 Aβ species in transgenic neurons. We conclude that Αβ40
or Αβ42 induce similar levels of neurotoxicity following TFW in these transgenic mice despite the difference in their amyloidogenic properties.
(IJCEP810008).
Key Words: Alzheimer’s disease, amyloid beta-peptide, transgenic mouse model, cortical neurons, cell death, trophic factor withdrawal
Full text PDF
Address all correspondence to: Qing Guo, MD, PhD, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma
City, OK 73104, E-mail: qing-guo@ouhsc.edu; najeeb-shirwany@ouhsc.edu
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