Publication Date:
2010-04-02
Description:
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death, severe cytological abnormalities, and markers of caspase activation and apoptosis, leading to the idea that tangles cause neurodegeneration in Alzheimer's disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are 'off pathway' to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091360/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Calignon, Alix -- Fox, Leora M -- Pitstick, Rose -- Carlson, George A -- Bacskai, Brian J -- Spires-Jones, Tara L -- Hyman, Bradley T -- AG 026249/AG/NIA NIH HHS/ -- AG08487/AG/NIA NIH HHS/ -- K99 AG033670/AG/NIA NIH HHS/ -- K99 AG033670-01A1/AG/NIA NIH HHS/ -- R01 AG008487/AG/NIA NIH HHS/ -- R01 AG008487-18/AG/NIA NIH HHS/ -- R01 AG026249/AG/NIA NIH HHS/ -- R01 AG026249-01/AG/NIA NIH HHS/ -- England -- Nature. 2010 Apr 22;464(7292):1201-4. doi: 10.1038/nature08890. Epub 2010 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20357768" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Brain/metabolism/pathology
;
Caspases/*metabolism
;
Cell Death
;
Enzyme Activation
;
Humans
;
Mice
;
Mice, Transgenic
;
Neurofibrillary Tangles/chemistry/enzymology/*metabolism/pathology
;
Neurons/enzymology/metabolism/pathology
;
Protein Processing, Post-Translational
;
Solubility
;
Time Factors
;
tau Proteins/chemistry/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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