New Inducible Models of Alzheimer's Disease
JAX® NOTES Issue 503, Fall 2006
Alzheimer's disease is the most common form of dementia in the elderly. It is characterized by β-amyloid plaques, neurofibrillary tangles, and synaptic and neuronal cell loss. The plaques are formed from Aβ peptides produced when β- and γ-secretases cleave the amyloid precurser protein (APP). The tangles form when the microtubule-associated protein tau (MAPT) is hyperphosphorylated.
The Jackson Laboratory Alzheimer's Disease Mouse Model Resource (ADMMR) is making available two new models that enable regulated expression of molecules involved in the etiology of Alzheimer's disease. The first model, B6C3-Tg(tetO-APPswe/ind)8-85Dbo/J (006004), allows controlled expression of a mutant form of human APP; the second model, C57BL/6-Tg(tetO-CDK5R1/GFP)337Lht/J (005706) allows controlled expression of a regulatory subunit of a kinase known to phosphorylate tau. Each model can be bred to a transgenic mouse that expresses either reverse tetracycline-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (tTA) to produce a bitransgenic mouse. Transgene expression in the bitransgenic mouse can then be regulated with the tetracycline analog doxycycline. The new models were originally designed to be bred with B6;CBA-Tg(Camk2a-tTA)1Mmay/J (003010), a transgenic mouse with a forebrain-specific promoter-linked tTA (Mayford et al. 1996).
The APP model was donated by Dr. David R. Borchelt, now at the McKnight Brain Institute. This model expresses a chimeric mouse/human APP carrying both the Swedish and Indiana mutations under the control of a tetracycline-responsive promoter element. Transgenic overexpression of the mutant APP produces high levels of Aβ40 and Aβ42, resulting in amyloid pathology that progresses from moderate in six-month old mice to severe in nine-month old mice. Suppression of transgene expression reduces Aβ production to control levels and stops progression of amyloid pathology, but existing amyloid deposits remain as long as six months after transgenic expression has been suppressed (Jankowsky et al. 2005).
The inducible tau kinase activator model was developed by Dr. Li-Huei Tsai, a Howard Hughes Medical Institute investigator who is now at MIT. This model can be made to express a regulatory subunit of cyclin-dependent kinase 5 ("p25"). When the transgene is expressed for a prolonged period, the mice exhibit elevated p25/Cdk5-related hyperphosphorylation of tau, leading to neurofibrillary tangle pathology, neuronal cell loss, and brain atrophy (Cruz et al. 2003). It has also been shown that, though prolonged expression of the transgene leads to impaired long-term potentiation (LTP) and memory deficits (as expected), short-term expression of the transgene enhances LTP and improves learning and memory (Fischer et al. 2005). Therefore, this model is useful both as a model of neurodegenerative disease and as a tool for studying synaptic plasticity (see use restrictions at the JAX® Mice Web site).
View for more information on the ADMMR, including a list of available models. View for more information on Alzheimer's disease.
References
Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH. 2003. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471-483.
Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH. 2005. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825-38.
Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA. Younkin SG, Borchelt DR. 2005. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2, e355.
Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER. 1996. Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678-83.
