Aβ-induced neurodegeneration is limited in APP and APP+PS1 transgenic mice. In middle-aged APP+PS1 transgenic mice, we found significantly increased Bcl-2 expression. The increase in Bcl-2 is restricted to amyloid-containing brain regions and is not found at young ages, suggesting that Aβ deposition is the stimulus for increased Bcl-2. Western blot results were confirmed with immunohistochemistry, and qRT-PCR. In addition, we found that APP transgenic mice were protected from neurotoxicity caused by an injection of bak BH3 fusion peptides, known to induce apoptosis by antagonizing bcl protein activity. Nissl and fluorojade stained slides showed that the active bak BH3 peptide caused substantial neuronal loss in the dentate gyrus and CA3 regions of nontransgenic, but not APP mice. The inactive mutant bak BH3 peptide did not cause degeneration in any mice. These data demonstrate that the increased Bcl-2 expression in brain regions containing Aβ deposits is associated with neuroprotection.
KeywordsBax; APP+PS1 transgenic mice; Alzheimer's disease; neurotoxicity; Aβ; apoptosis The amyloid cascade hypothesis states that the dysregulation of amyloid precursor protein (APP) processing and Aβ production are the major causes for neuronal death and dysfunction leading to dementia in Alzheimer's disease (Hardy and Selkoe, 2002). Genetic and environmental factors, such as APP or PS-1 mutations, cause an accumulation of Aβ which forms diffuse and compact plaques. These plaques are thought to cause oxidative stress, activate microglia and astrocytes, causing cytokine release, inflammation and altered ionic homeostasis, culminating in cytotoxicity and neuronal death.The Aβ peptide can directly induce neuronal apoptosis in vitro (Pike et al., 1993); (Hensley et al., 1995); (Schubert and Chevion, 1995); (Wogulis et al., 2005). Intracellular Aβ may activate apoptosis by interacting with the endoplasmic reticulum and endosomes and by binding to alcohol dehydrogenase within the mitochondria (Dickson, 2004). Aβ also induces changes in nitric oxide production and mitochondrial activity facilitating apoptosis (Keil et al., 2004). InCorresponding author: Dave Morgan, Alzheimer Research Laboratory, University of South Florida 12901 Bruce B. Downs Blvd MDC Box 9 Tampa, FL 33612, Scientist.dave@gmail.com Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Aβ-induced neuronal toxicity is limited in the APP transgenic mouse models of AD. A modest reduction in hippocampal neurons was found in old APP23 mice, but the cortical neuron census was unaffected despite extensive amyloid deposition (Calhou...