Tau seeding and spreading model

Tau protein and Alzheimer ’s disease

The hallmarks of Alzheimer’s disease seen in post-mortem brain tissue of patients are extracellular deposits of the protein amyloid beta (plaques) and intracellular inclusions of the protein tau (tangles). Evidence from postmortem studies shows that tau pathology in Alzheimer’s disease starts in the entorhinal cortex and spreads throughout the brain. Recent PET studies show that the increase in tau pathology correlates well with the decline in cognitive function seen in Alzheimer’s disease patients.

Tau mouse models

Numerous transgenic tau mouse models are widely used to study the efficacy of therapeutics that are aimed at preventing the initiation and/or spread of tau pathology. These models overexpress human tau with frontotemporal dementia-linked mutations throughout the nervous system, such as the P301L and P301S mutation. The overexpression of these mutated forms of tau result in a global induction of tau pathology and behavioral phenotypes that are not related to Alzheimer’s disease, such as profound motor function impairments.

Tau seeding model at Sylics

In the human brain, cell to cell spread of tau pathology is thought to play a crucial role in disease progression. To better mimic this tau spreading, a mouse model induced by ‘seeding’ of tau pathology is required to closely mimic human tau pathology. The source of the tau seeds as well as the genetic background in which the seeds are injected have a large effect on the rate at which tau pathology emerges. At Sylics, we compared the emergence of pathology after local intra-hippocampal infusion of various tau seed preparations prepared by our collaborators. Seeds were injected in different genetic backgrounds. Seeding with tau seeds isolated from human AD brain tissue was most effective in inducing AT8-positive tau in htau mice. In htau mice, AT8-positive tau structures were observed in hippocampus as well as other brain regions at 12 and 26 weeks.

Preclinical proof of concept studies

Typical proof of concept studies at Sylics employ administration of the therapeutic substance prior to tau seeding, or co-infusion of tau seeds with the therapeutic substance. The development and spread of AT8 positive tau is taken as measure of efficacy. For further information on this model and possibilities, please contact us at info@sylics.com.