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.