06 Aug 2002

A key controversy revolved around the value of available mouse models. Current Aβ models are only partial models of AD; they recapitulate amyloid deposition, gliosis around neuritic plaques, subtle synaptic changes and neuritic damage, and subtle learning and behavioral deficits. Their key shortcomings are that most do not exhibit neurofibrillary pathology, and none show the massive neuronal loss seen in AD. Transgenic models of tau pathology also mimic only parts of the disease. Defenders of the models said that a large number of strains have independently produced similar data. Technical criticisms included the possibility of artifacts caused by overexpression of AβPP with physiologically irrelevant promoters, the possibility of variegated silencing of transgenes, and the use of cDNA transgenes rather than genomic DNA. Suggested improvements included generating knock-in strains to express human genes under the control of endogenous mouse regulatory regions, and the creation of a series of mice on a common background that are deleted for different parts of suspected pathways. Suggestions made with regard to current strains involved setting up modifier screens to identify additional risk factor genes, and crossing them to strains deleted for other genes in AD linkage regions.

Recommendations:

1. Investigate existing resources in mouse genetics or set up a new program to systematically create a series of knockouts focusing on AD-relevant pathways using a common genetic background.

2. Cross the best AβPP mice to other knockouts to find modifiers (candidates might include the ER stress mouse or the oxidative stress mouse). Cross the best AβPP mice with strains deleted for genes in the AD linkage region.

3. Support knock-in strains of AβPP and other genes of interest.

4. Support creation of models for AD-relevant measures of plasticity: electrophysiology/LTP and synaptic markers.

5. Study how mouse models differ from humans to identify human AD modifier genes.

6. Support development of portal for repeated CSF withdrawal and drug delivery to mouse spinal cord.

7. Establish mechanisms to facilitate getting the needed strains into the hands of willing investigators.

—Gabrielle Strobel ,June Kinoshita