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Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau
Van der Jeugd A, Hochgräfe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L et al.. Acta neuropathologica, 2012-04-25
Topic: Brain proteins, microglia and lab models
Neurofibrillary lesions of abnormal Tau are hallmarks of Alzheimer disease and frontotemporal dementias. Our regulatable (Tet-OFF) mouse models of tauopathy express variants of human full-length Tau in the forebrain (CaMKIIα promoter) either with mutation ΔK280 (pro-aggregant) or ΔK280/I277P/I308P (anti-aggregant). Co-expression of luciferase enables in vivo quantification of gene expression by bioluminescence imaging. Pro-aggregant mice develop synapse loss and Tau-pathology including missorting, phosphorylation and early pretangle formation, whereas anti-aggregant mice do not. We correlated hippocampal Tau pathology with learning/memory performance and synaptic plasticity. Pro-aggregant mice at 16 months of gene expression exhibited severe cognitive deficits in Morris water maze and in passive-avoidance paradigms, whereas anti-aggregant mice were comparable to controls. Cognitive impairment of pro-aggregant mice was accompanied by loss of hippocampal LTP in CA1 and CA3 areas and by a reduction of synaptic proteins and dendritic spines, although no neuronal loss was observed. Remarkably, memory and LTP recovered when pro-aggregant Tau was switched-OFF for ~4 months, Tau phosphorylation and missorting were reversed, and synapses recovered. Moreover, soluble and insoluble pro-aggregant hTau40 disappeared, while insoluble mouse Tau was still present. This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction. It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau. Therefore, our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking. It offers potential to evaluate drugs with regard to learning and memory performance.
Key findings
- Moreover, soluble and insoluble pro-aggregant hTau40 disappeared, while insoluble mouse Tau was still present.
- This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction.
- It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau.
- Therefore, our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking.
- It offers potential to evaluate drugs with regard to learning and memory performance.
Study details
- Evidence strengthLow
How this study scored 40/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2012 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22532069) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., et al. (2012). Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta neuropathologica. https://doi.org/10.1007/s00401-012-0987-3
Vancouver
Van der Jeugd A, Hochgräfe K, Ahmed T, Decker JM, Sydow A, Hofmann A, et al. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta neuropathologica. 2012. doi:10.1007/s00401-012-0987-3. PMID: 22532069.
BibTeX
@article{vanderjeugd2012-22532069,
author = {Van der Jeugd, A. and Hochgräfe, K. and Ahmed, T. and Decker, J. M. and Sydow, A. and Hofmann, A. and Wu, D. and Messing, L. and others},
title = {{Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau}},
journal = {Acta neuropathologica},
year = {2012},
doi = {10.1007/s00401-012-0987-3},
pmid = {22532069},
url = {https://doi.org/10.1007/s00401-012-0987-3}
}