Transgenic mouse expressing human tau gene

Details Transgenic mouse expressing human tau gene Transgenic mouse expressing human tau gene

2000-03-02

2003-07-15

Crouch, Deborah (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

Transgenic nonhuman animal

C800S003000, C800S009000, C800S012000, C800S021000, C800S022000, C435S455000, C435S463000, C435S320100, C435S325000

Reexamination Certificate

active

06593512

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns transgenic animals that are useful as models of Alzheimer's disease, other neurodegenerative diseases, and methods of use thereof.
2. Description of the Related Art
Currently affecting some 4,000,000 Americans, Alzheimer's Disease (AD) is the leading cause of dementia and the fourth leading cause of death. Over a typical 10 to 20 year course, AD is characterized by progressive memory loss and the eventual death of the patient. These behaviors are associated with the presence of amyloid plaques, cerebrovascular amyloid deposits and neurofibrillary tangle lesions in the patients' brains. Multiple genes have been associated with familial and sporadic forms of Alzheimer's indicating that different genes can initiate changes that culminate in this rather uniform phenotype.
Existing therapies are palliative and provide only temporary symptomatic relief for a small portion of those afflicted with the disease. At present, there are no effective therapies to slow or halt the progression of the disease thus creating a large unmet medical need for afflicted patients, their families and care givers. Further compounding this picture, the prevalence of Alzheimer's increases with age such that about half of all persons age 85 and older have AD. As our health care system continues to improve the health of Americans, the numbers of Alzheimer's patients will continue to rise in accord with their increased lifespan.
As discussed by Jennifer Kwon at the Alzheimer's Research Forum web page, Tau is a microtubule associated protein that is involved in microtubule assembly and stabilization in the human brain. In adult human brain, six tau isoforms are produced from a single gene by alternative mRNA splicing. They differ from each other by the presence or absence of 29- or 58-amino-acid inserts located in the amino-terminal half and 31-amino-acid repeats located in the carboxy-terminal half. Inclusion of the latter, which is encoded by exon 10 of the tau gene, gives rise to the three tau isoforns that each have four repeats. In normal cerebral cortex, there is a slight preponderance of 3-repeat over 4-repeat tau isoforms. These repeats and some adjoining sequences constitute the microtubule-binding domain of tau (Goedert et al., 1998, Nat Med, April 1999, 5(4): 454-7).
One of the characteristics of AD is the presence of neurofibrillary tangles, intraneuronal deposits of paired helical filaments made of hyperphosphorylated Tau. Abnormal deposit of Tau is also seen in other neurodegenerative disorders, including progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBD), and frontotemporal dementias (FTD) (synonomous with Frontal Temporal Dementias). Variability in the tau gene has been shown to be a risk factor for PSP (Conrad et al., Ann Neurol, February 1997, 41(2): 277-81). Recent studies suggest that mutations of the TAU gene (responsible for coding for the Tau protein) may be involved in these Tau protein abnormalities, possibly contributing to the onset of some of these neurodegenerative disorders.
Pathologically, frontotemporal atrophy is a consistent finding, which may be accompanied by basal ganglia atrophy and substantia nigra depigmentation. Many families have tau-positive inclusions either in neurons or in neurons and glia. And where linkage data was available, familial forms of FTD were linked to chromosome 17. A consensus conference decided that the term FTD with parkinsonism linked to chromosome 17 (FTDP-17) was preferred as it stressed the common clinical and pathologic features shared by this autosomal-dominant, neurodegenerative condition (Foster et al., Ann Neurol, June 1997, 41(6): 706-15).
In 1998, a series of papers reported that mutations in tau were associated with FTDP-17 (Hutton et al., Nature, June 1998, 393(6686): 702-5; Poorjak et al., Ann Neurol, June 1998, 43(6): 815-25; and Spillantini et al., Proc Natl Acad Sci U S A, April 1997, 94(8): 4113-8). The mutations causing various forms of FTD are of two major types (Goedert et al., 1998), coding mutations and intronic mutations. Most coding mutations occur in the microtubule-binding repeat region or very close to it. These potentially lead to a partial loss of function of tau with reduced tau binding to microtubules (Hong et al., Science, December 1998, 282(5395): 1914-7; Dayanandan et al., FEBS Lett, March 1999, 446(2-3): 228-32; Hasegawa et al., FEBS Lett, October 1998, 437(3): 207-10; Goedel et al., 1998; and Spillantini and Goedert, Trends Neurosci October 1998; 21(10):428-33). There is also convincing evidence that tau missense mutations directly increase the tendency of tau to aggregate into filaments (Nacharaju et al., FEBS Lett, March 1999, 447(2-3): 195-9; and Goedert et al., FEBS Lett, May 1999, 450(3): 306-11). Some missense mutations (G272V in exon 9, V337M in exon 12 and R406W in exon 13) affect all isoforms produced, while P301L only alters those isoforms with four repeats. The intronic mutations are all near the splice donor site of the intron following exon 10. By presumably destabilizing a predicted RNA stem-loop, there is a change in the ratio of 3-repeat to 4-repeat isoforms (Hutton et al., 1998; Spillantini, Murrell et al., Proc Natl Acad Sci U S A, June 1998, 95(13): 7737-41). There are two coding mutations, N279K and S305N, which appear to enhance splicing of exon 10 rather than to reduce microtubule assembly (D'Souza et al., Proc Natl Acad Sci U S A, May 1999, 96(10): 5598-603; Hasegawa et al., FEBS Lett, January 1999, 443(2): 93-6). Conversely, the delK280 mutation reduces splicing (D'Souza et al. 1999).
Although the various mutations in tau are associated with frontotemporal dementia, distinctive clinical and pathologic features seem to be found with particular mutations. It is clear that the variable tau isoform content in FTDP-17 tangles is largely explained by the nature of the mutations: Mutations in or near exon 10 result in tangles consisting predominantly of 4-repeat tau, while mutations outside exon 10 are associated with tangles with both 4-repeat and 3-repeat tau. These latter tangles seem to result in filament morphology that is very similar to that seen in Alzheimer's disease. The filament morphology of 4-repeat tangles is more variable but generally they have a longer periodicity than the PHFs seen in AD. Mutations in exon 10 generate glial inclusions and those outside exon 10 generally do not (but there is at least one exception, in press).
Improved assays of the functional effects of tau mutations may enable us to link the size of these effects to the severity of the clinical phenotype. It already seems likely that a large effect on microtubule-binding and tau aggregation correlates with a more severe phenotype. In addition, the exon 10 splice site mutations appear to relate to clinical phenotype based on the degree to which they disrupt splicing (the +16 mutation appears to be the mildest with incomplete penetrance, while the +3 and +14 are most severe). It is, therefor, desirable to be able to provide a mammalian model for testing the effect of the human TAU gene and its mutations on neurodegenerative physiology and behavior.
In this regard, U.S. Pat. No. 5, 767,337 to Roses et al. describes the creation of human apolipoprotein-E, isoform-specific transgenic mice in apolipoprotein-E deficient, knockout mice. These mice are useful as an animal model of one type of Alzheimer's disease. Nevertheless, because of the complexity of this disease and/or syndrome, there remains a need for additional animal models of Alzheimer's disease, and other neurodegenerative diseases.
SUMMARY OF THE INVENTION
Accordingly, it is a purpose of the present invention to provide an animal model for analyzing Alzheimer's, Frontal Temporal Dementia, Parkinson-like, and other neurodegenerative diseases.
It is another purpose of the present invention to provide a bigenic mouse that can be used to determine whether a compound ca

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