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The Journal of Neuroscience, March 19, 2008, 28(12):3051-3059; doi:10.1523/JNEUROSCI.5620-07.2008

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Neurobiology of Disease
Lack of Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease after Overexpression of the Anti-Apoptotic Protein Bcl-2

Troy T. Rohn,1 Veera Vyas,1 Tatiana Hernandez-Estrada,2 Kathryn E. Nichol,2 Lori-Ann Christie,2 and Elizabeth Head2

1Department of Biology, Boise State University, Boise, Idaho 83725, and 2Institute for Brain Aging and Dementia, Department of Neurology, University of California, Irvine, Irvine, California 92697

Correspondence should be addressed to Troy T. Rohn, Department of Biology, Science/Nursing Building, Room 228, Boise State University, Boise, ID 83725. Email: trohn{at}boisestate.edu

Alzheimer's disease (AD) is characterized by the accumulation of plaques containing β-amyloid (Aβ) and neurofibrillary tangles (NFTs) consisting of modified tau. Although Aβ deposition is thought to precede the formation of NFTs in AD, the molecular steps connecting these two pathologies is not known. Previous studies have suggested that caspase activation plays an important role in promoting the pathology associated with AD. To further understand the contribution of caspases in disease progression, a triple transgenic Alzheimer's mouse model overexpressing the anti-apoptotic protein Bcl-2 was generated. Here we show that overexpression of Bcl-2 limited caspase-9 activation and reduced the caspase cleavage of tau. Moreover, overexpression of Bcl-2 attenuated the processing of APP (amyloid precursor protein) and tau and reduced the number of NFTs and extracellular deposits of Aβ associated with these animals. In addition, overexpression of Bcl-2 in 3xTg-AD mice improved place recognition memory. These findings suggest that the activation of apoptotic pathways may be an early event in AD and contributes to the pathological processes that promote the disease mechanisms underlying AD.

Key words: amyloid precursor protein; β-amyloid; caspase; mouse model; neurofibrillary tangles; plaques; tau; Bcl-2

Received Sept. 14, 2007; revised Jan. 28, 2008; accepted Jan. 30, 2008.

Correspondence should be addressed to Troy T. Rohn, Department of Biology, Science/Nursing Building, Room 228, Boise State University, Boise, ID 83725. Email: trohn{at}boisestate.edu
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