New Mouse Models Better Mimic Tauopathy, Alzheimer's

  I heard a bad alzheimer's joke.  

if you are going to get Alzheimers', first, become a mouse. 

 Treatments that worked on mice have failed in human trials innumerable times, (except for Light and Sound Therapy at 40Hz - Tsai's 'Bringing Gamma Back' trial when it was recreated with humans by Cognito.)

 One problem seems to have been that the majority of research mice's genetic was based on the PS1 gene from Early Onset, but only 1% of Alzheimers's cases is caused by Early Onset.

Also, the mice were not created to have Tau tangles.  Then when they knocked in Tau tangles, it was in young mice.  Mice aren't usually aged to match human disease progression.

“If you model having dementia when the mouse is 4 months old, you probably did something very different than what happens in a human, because that’s just not how that works,” Koob said

To address this problem, the NIH in 2019 funded the AD-related dementias gene replacement project, of which Koob is the PI.

 It aims to evaluate the impact of MAPT mutations within the context of the genomic sequence. Koob and colleagues developed a gene-replacement technology that allows them to take out the mouse MAPT gene and substitute in the entire human MAPT gene.

They produced two different wild-type versions of the mice.

 In H1.0, all 190,000 base pairs of the human sequence are of the H1 haplotype;

 in H2.1, the first 23,000 base pairs are H1, and the next 167,000 base pairs are of the H2 haplotype.

 The H1 haplotype block is more common, and carries more risk of neurodegeneration than the H2 haplotype (e.g., Mar 2019 news; Sep 2005 news).

 To induce a disease phenotype in these wild-type mice, the scientists inflicted a mild traumatic brain injury. After one week, they saw an accumulation of phosphorylated tau near the TBI site.