. Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. J Neurosci. 2011 Jul 20;31(29):10427-31. PubMed.

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  1. A growing body of literature supports a key role of cellular prion protein (PrPc) in Alzheimer's pathophysiology. Recent reports have demonstrated that endogenous Aβ oligomers from both mouse and human AD brain bind PrPc, and that PrPc is required for impairment of synaptic plasticity and toxicity caused by both synthetic and human-derived Aβ oligomers, in vivo and in vitro (1-4). While we observed previously that PrPc is essential for AD transgene-induced deficits in survival, synapse loss, and spatial memory in the APPswe/PS1ΔE9 line (5,6), here Lennart Mucke and colleagues report that PrPc is not required for phenotypes in the J20 line (7). The most critical differences between their experiments and those of others is the AD transgenic line studied and the age of onset for behavioral deficits. Previous reports showed that the J20 mice are behaviorally impaired at the youngest ages at which they have been tested, perhaps due to the high Aβ levels in this strain (8,9). There is not evidence for a progressive behavioral deficit in these mice, as exists in AD, and the behavioral changes are fully developed by early adulthood. In contrast, the APP/PS1 line, which we studied, has normal spatial memory at three to six months, and becomes impaired during aging (5,10). The most plausible conclusion is that PrPc is required for adult-onset AD transgene-driven progressive disease, whereas developmental-onset deficits in the J20 occur by a different mechanism. The developmental disorder is PrP independent, but the late-onset progressive process is PrP dependent. Further study may provide important information about the action of AD transgenes at different ages.

    There are also some minor issues with regard to seizures and survival in the new paper. The seizure-related data from Cissé et al. are limited, focusing only on single EEG spikes. In our own unpublished work showing PrP dependence in APPswe/PS1ΔE9 mice, and in Mucke’s previous studies, full seizures were recorded. With regard to spikes, the new paper has very low numbers of single spikes per hour compared to the previous data on J20. For example, the J20 Prnp-/- had 15 spikes per hour and the J20 Prnp+/+ had seven to eight spikes per hour. However, the previously published J20 control data had over 100 spikes per hour (11), and in the 2007 Neuron article, the number was 300-3,000/hour (12). Compared to these historical controls, spikes are dramatically suppressed in the J20 Prnp-/- group compared to J20. With this variation, it seems difficult to make a conclusion about a Prnp effect one way or the other.

    On survival, the suggestion that survival is worse without PrP is not consistent with the data in the new paper. If one examines death from day zero to 270, rather than just 30-270, Prnp makes no difference (compared to animals with no APP transgene, 55 percent and 52.5 percent of J20 animals with and without Prnp survive, respectively). For survival from day 30-270, the data from Cissé et al. for the J20 Prnp-/- group seem identical to the published data on J20 mice (13); both have survival rates of 80-85 percent. It seems that there is unusually good survival in the J20 Prnp+/+ group in the new study. In addition, the Mantel Cox survival analysis does not seem to be correct (reported P A detailed understanding of the differences between transgenic AD mouse models should help define Aβ signaling pathways most relevant to AD and their mechanistic relationship to PrPc. Direct comparison of Aβ species and concentrations in different lines at different ages may be informative. The progressive nature of the behavioral symptoms after normal development is likely to be most critical for modeling AD in mice.

    References:

    . Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat Commun. 2011 Jun 7;2:336. PubMed.

    . The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication. EMBO J. 2011 May 18;30(10):2057-70. PubMed.

    . Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues. J Biol Chem. 2010 Aug 20;285(34):26377-83. PubMed.

    . Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011 May 18;31(20):7259-63. PubMed.

    . Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci. 2010 May 5;30(18):6367-74. PubMed.

    . Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse. BMC Neurosci. 2010;11:130. PubMed.

    . Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. J Neurosci. 2011 Jul 20;31(29):10427-31. PubMed.

    . Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice. Neurobiol Aging. 2008 Feb;29(2):253-66. PubMed.

    . Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci. 2010 Jan 6;30(1):372-81. PubMed.

    . Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice. J Neurosci. 2006 Dec 20;26(51):13279-86. PubMed.

    . Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.

    . Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

    . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

  2. I fully understand and share Dr. Strittmatter’s eagerness to resolve the controversy surrounding his original findings. As pointed out in our paper, the different effects of PrPC ablation on Aβ-induced functional deficits observed by different investigators might stem from differences in experimental protocols, hAPP lines, and Prnp–/– strains. We hope that additional independent groups with extensive experience in transgenic modeling, electrophysiology, and behavioral phenotyping will help address these possibilities.