• Home
• Lageplan
• Forschung
• Funding
• Publikationen
• Links
• Graduierungen
• Dr. rer. nat.
  in Göttingen
• Alzheimer Therapie Kupferstudie

Intraneuronal Aß and neuron loss in AD and transgenic mouse models

Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers’s disease (AD) have been proven to be valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less successful. We, and others, have previously reported that intraneuronal accumulation of Aß peptides precedes plaque deposition in transgenic AD mouse models [1]. In APP/PS1KI mice, we have shown that transient intraneuronal Aß rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex [2]. Intraneuronal Aß accumulation correlates with neuron loss also in other brain areas including hippocampus [3] or cholinergic motor nuclei [4], as well as frontal cortex neurons in the 5XFAD mouse model of AD [5]. In addition, we have recently demonstrated that intraneuronal accumulation of pyroglutamate-modified Aß3-42 triggers neurodegeneration and neurological deficits in a novel transgenic mouse model [6]. Moreover, intraneuronal Aß is detected in neurons in human AD brain correlating with the most important genetic risk factor ApoE4 [7].
The presence of intraneuronal Aß in the commonly used 3xTg mouse model of AD was recently debated as it has been published that only APP instead of Aß accumulates within neurons. We have recently shown that indeed APP accumulates within neurons, but by the use of antibodies detecting neo-epitopes, we can also confirm the presence of Aß peptides within neurons in this model [8].

References:

• Wirths, O., et al., Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett, 2001. 306(1-2): p. 116-20.
• Christensen, D.Z., et al., Transient intraneuronal Abeta rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol, 2008. 116(6): p. 647-55.
• Breyhan, H., et al., APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy. Acta Neuropathol, 2009. 117(6): p. 677-685.
• Christensen, D.Z., T.A. Bayer, and O. Wirths, Intracellular Abeta triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer’s disease. Neurobiol Aging, 2010. 31(7): p. 1153-1163.
• Jawhar, S., et al., Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging, 2010.
• Wirths, O., et al., Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol, 2009. 118: p. 487-496.
• Christensen, D.Z., et al., Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol, 2010. 119: p. 555-566.
• Wirths, O., et al., AßPP accumulation and/or intraneuronal amyloid-ß accumulation? The 3xTg-AD mouse model revisited. J Alzheimer Dis, in press