Localized gene transfer has produced the first rat model of neurofibrillary tangles, announce the authors of a report in the January 2004 American Journal of Pathology. The researchers, led by Ron Klein of Louisiana State University Health Sciences Center in Shreveport, also produced tau pathology in the hippocampus of PS-1/APP double-transgenic mice with their viral vector.
Transgenic mice with neurofibrillary tangles (NFTs) can now be created using the P301L tau mutation that causes the tauopathy frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, tau pathology in these mice takes time—and lots of money—to develop, and the authors write that it is possible that the nervous system adapts to the transgene during development, reducing the relevance of this pathology to Alzheimer's disease. Enter the virus. In addition to addressing these two issues, viral introduction of transgenes offers other advantages, such as within-animal comparisons of unilateral injections, or the ability to work with larger animals such as rats.
Following the groundbreaking work of Rusty Gage and colleagues in modeling polyglutamine repeat disorders via a viral vector (Senut et al., 2000), the approach has been applied to other disease-associated genes, including alpha synuclein (see ARF related news story). In the current report, Klein and colleagues describe their success with a vector construct that combines the P301L tau mutation with the hybrid cytomegalovirus/chicken β-actin (CBA) promoter and the 3' enhancer woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). When transfected into the medial septal region of the basal forebrain of three-month-old male Sprague-Dawley rats, this construct produced tau expression confined to this area within three weeks. By four months, the researchers identified NFTs with immunoelectron microscopy. Constructs that did not include the WPRE were less successful in producing tau expression.
The researchers also report some success with injecting the vectors into the hippocampi of two-month-old PS-1/APP mice, attempting to add tau pathology to a line that produces β-amyloid pathology. Immunolabeling for mutant tau revealed the presence of "tau pretangles" adjacent to amyloid deposits in the transfected hippocampi of these mice at the age of 14 months.
The ability to work in rats, the authors write, will make it easier for researchers to employ various pharmacological and behavioral techniques to probe the effects of tau mutations on the development of NFTs and on Alzheimer's pathology. "For example, the influence of the aged brain can be evaluated by comparing results from vector injections at the same dose and time interval, in either young or old rats," the authors note.—Hakon Heimer
- Senut MC, Suhr ST, Kaspar B, Gage FH. Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain. J Neurosci. 2000 Jan 1;20(1):219-29. PubMed.
- Klein RL, Lin WL, Dickson DW, Lewis J, Hutton M, Duff K, Meyer EM, King MA. Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol. 2004 Jan;164(1):347-53. PubMed.