Alzheimer’s Disease: next generation mouse models

Alzheimer’s Afternoons Seminar Series (March 31) Gareth Howell

This seminar was presented by Dr. Gareth Howell, Associate Professor and the Diana Davis Spencer Foundation Chair for Glaucoma Research at the Jackson Lab.  His premise was that progress in AD research has been hindered by poor mouse models.  He is a member of the MODEL-AD group, a collection of hundreds of researchers working to create and test next-generation mouse models.

He began by describing new mouse models developed with human apoe4 genes.

Murine apoE (the gene in mice) and human apoE4 are not the same, making wild type mice relatively useless for the study of Alzheimer’s disease.  For example, murine apoe4 vs human apoe4 have quite different tendencies to facilitate plaque or CAA formation.  As result, transgenic mice wherein murine apoe genes are replaced by human apoe4 (or apoe3 or apoe2) genes are very valuable.

Thanks to the work of those at the Jackson Labs (and many other institutions) many other types of mice expressing other AD risk genes are available.

He noted that mice carrying human apoe4 genes exhibit a break-down in brain vessels, specifically fibrin leakage into the brain, but only in mid-life mice (not at younger ages).  In these mice blood flow was reduced, as visualized by PET scans. They are currently exploring the potential benefits of exercise to correct this in 4/4 (vs. 3/3) mice.  Thus far, they have found that apoe4/4 mice are just as good at exercise and had no observed differences when young.  They also found that, in these mice, exercise helped to prevent the problems apoe4/4 mice normally developed with increasing age but only if the exercise was started when mice were young.

In general, he noted that neither human apoe4/4 genes nor older age are sufficient by themselves to cause AD in these mice. Some other trigger is necessary.

They also developed mice carrying human TREM2 genes.

TREM2 is shorthand for “triggering receptor expressed on myeloid cells 2”.  It is a receptor found on the surface of many types of cells, including microglia, that is important for the functioning of the innate immune system.  Some alleles (genetic variants) of the TREM2 gene are associated with late-onset Alzheimer’s disease and related dementias.

Dr. Howell made crosses to create of mouse populations with particular combinations of APOE and TREM2 genotypes.  They measured mouse “frailty” in these various populations and noted no differences.  They also noted that apoe4 protein levels – the total amount of apoe protein measured – don’t seem to change with age in these mice.

Dr. Howell observed that amyloid beta accumulation seems to be a trigger to cause AD symptoms – but this is often inconsistent.  This is in line with many previous observations that the accumulation of Aβ in the brain is often, but not always, associated with cognitive decline.  Aβ accumulation is just one possible – though probably common – trigger.

Together, this large group of researchers collected data suggesting that apoe4 mice tend to have a more fragile central nervous system, especially when older.

The most impressive aspect of Dr. Howell’s seminar was the enormous amount of work done with the MODEL-AD group to generate better mouse models of LOAD.