Alzheimer's Disease-Related Strain

JAX® NOTES Issue 488, Winter 2002

Alzheimer's Disease (AD) is widely recognized as a serious public health problem. The number of new cases in the United States is currently estimated at 360,000 annually, a number that is expected to rise as the average age of populations in industrialized countries increases1. One of the hallmarks of AD is the presence of extracellular amyloid deposits in the brain, most often observed in the tissues of the cortex, hippocampus, and amygdala. The primary constituents of these plaques are fibrillar aggregates of a 4kD cleavage product (termed ß amyloid, or Aß) derived from the amyloid beta (A4) precursor protein (human gene symbol: APP). The APP gene consists of at least 18 exons from which several alternative transcripts, containing 695, 714, 751, and 770 amino acids, arise2,3. Among the mutations that have been described in the human APP gene is a set of double point mutations that have been shown to co-segregate with the occurrence of an early-onset form of AD in two large Swedish families. These mutations, collectively referred to as the 'Swedish' mutation (APPswe) lie adjacent to the Aß cleavage site and result in a 6-8 fold increase in the Aß product4.

Mutations found to enhance the deposition of Aß also occur in the presenilin 1 gene (human gene symbol: PSEN1).  The PSEN1 gene encodes an integral membrane protein consisting of at least 12 exons. Two such mutations A246E (where glutamic acid replaces alanine at position 246) and ΔE9 (where exon 9 is mis-spliced), are each associated with an early onset familial form of AD.

Double transgenic mice, that express a chimeric mouse/human APPswe transgene in conjunction with a PSEN1 transgene bearing the ΔE9 mutation, were created by Dr. David Borchelt of Johns Hopkins School of Medicine. Histological examination reveals that amyloid plaques appear in the brain tissue of these mice much earlier than in mice bearing only the APPswe transgene5.

Dr. Borchelt recently improved on this model. In contrast to the initial double transgenic model that was created by mating single transgenic animals, the newer model was made by simultaneously co-injecting the transgenic constructs into the founder mouse pronucleus6. Co-injection frequently results in both transgenes integrating into the same chromosomal locus. An advantage of co-integration into a single locus is an increased percentage of double transgenic offspring over that expected from single transgenic matings. Although the expression of each transgene is directed by a mouse prion protein promoter, as in the previous model, the co-injected double transgenic mouse surprisingly exhibits amyloid deposits at an earlier age than reported for the previous models (see Table 1).

Table 1. Mutation and corresponding age of onset based on detection of amyloid deposits

Mutation Age When Amyloid Deposits Detected
APPswe 18 months
APPswe/PSEN1(A246E) 9 months
APPswe/PSEN1(DeltaE9) (co-injected)
B6C3-Tg(APP695)85Dbo Tg(PSEN1)85Dbo (Stock Number 004462)		 6 months7

Dr. Borchelt has kindly donated his co-injected APPswe/PSEN1(DeltaE9) strain, called B6C3-Tg(APP695)85Dbo Tg(PSEN1)85Dbo (Stock Number 004462), to the Induced Mutant Resource at The Jackson Laboratory, where it complements a growing number of AD-related mutant mouse strains.  If you are interested in ordering these mice, please contact Customer Service at 800.422.MICE or 207.288.5845.

REFERENCES

  1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 9:1337-1342.
  2. Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD. Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice. Nat Genet 1993; 5:22-30.
  3. Wong PC, Cai H, Borchelt DR, Price DL. Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 2002; 5:633-639.
  4. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. Mutation of the beta-amyloid pre-cursor protein in familial Alzheimer's disease increases beta-protein production. Nature 1992; 360:672-674.
  5. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amylod precursor proteins. Neuron 1997; 19:939-945.
  6. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 2001; 17:157-165.
  7. Unpublished observations from Dr. Borchelt.