Original Article Cortical Neurons Transgenic for Human Aβ40 or Aβ42 Have Similar Vulnerability to Apoptosis despite Their Different Amyloidogenic Properties

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 Aβ40 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 Aβ40 or Aβ42 in the absence of human amyloid beta protein precursor (APP) overexpression. It was found that mice expressing Aβ42, but not Aβ40, 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 Aβ40 or Aβ42 induce similar levels of neurotoxicity following TFW in these transgenic mice despite the difference in their amyloidogenic properties.