General Information

Transgene: Bgl II-Sma I fragment of APP-695 cDNA (bb 1769-2959) was cloned into a modified form of plasmid pRSV

Promoter: in which the Rous sarcoma virus promoter is replaced with the dystrohpin neural promoter. 

Coding Region:  Transgene is place downstream simian virus 40 splice and polyadenylylation sequences.

Flag Sequence (Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys), preceded by a methionine, to the N-terminus of APP-C100

Mouse Strain:  C58BL/6 x SJL. 

Phenotype

Neuropathological Analysis:

As early as 4.5 months of age, APP-C100 mice showed appearance of oddly shaped secondary lysosomes that were immunoreactive with antibodies directed against portions of APP-C100.  In older mice, these structures took the form of abundant deposits of dense, granular material in the hippocampal formation.

Numerous pyramidal cells in various states of degeneration could be found throughout the dentate gyrus and ammon's horn in the 23-month-old and 28-month-old APP-C100 mice, respectively.

At age of 1 year, C100 mice display a significant number of large lucent pyramidal neurons containing irregular cytoplasmic accumulations of atypical secondary lysosomes, and an increased neurofilament concentration in unmyelinated axons.

Cytoskeletal and synaptic degeneration observed in the APP-C100 mice.

FLAG-APP-C100:  The FLAG sequence is used to distinguish the transgene product from the endogenous APP gene product.

FLAGAPP-C100 is less prone to aggregate than was C100, and that it bound with greater affinity than did C100 to a specific PC12 cell receptor that mediates the C100 toxicity, which suggests that C100, unlike Ab, is most deadly to neurons when it is in a nonaggregated form. Also unlike Ab, toxicity of C100 is receptor mediated and pH dependent.

Behavior

No gross motor or sensory abnormalities were apparent in the mice.  

All the mice exhibited normal righting, grasping and placing reflexes.  None of the mice floated excessively during any of the swim trials. No significant differences in Dark-cycle locomotor activities observed between transgenic and control mice.

In Morris water maze,  homozygous transgenic mice expressing Flag epitope-tagged APP-C100, relative to heterozygote Tg and control, showed significant deficits in cued, spatial and reversal performance. The degree of impairment of spatial learning in homozygous mice appears to be age-dependent.

Among heterozygotes, females were relatively more impaired in their spatial learning than were males.

Availibility

Contact Dr. Rachael Neve
202 MRC
McLean Hospital
115 Mill Street
Belmont, MA 02178

Patents:

Reference

Primary:

Neve RL, Boyce FM, McPhie DL, Greenan J, Oster-Granite ML. Transgenic mice expressing APP-C100 in the brain. Neurobiol Aging 1996 Mar-Apr;17(2):191-203. Abstract.

Associated:

Oster-Granite ML, McPhie DL, Greenan J, Neve RL. Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein. J Neurosci 1996 Nov 1;16(21):6732-41. Abstract.

Kammesheidt A, Boyce FM, Spanoyannis AF, Cummings BJ, Ortegon M, Cotman C, Vaught JL, Neve RL. Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain. Abstract.

Berger-Sweeney J, McPhie DL, Arters JA, Greenan J, Oster-Granite ML, Neve RL. Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 1999 Mar 20;66(1-2):150-62. Abstract.