Alzheimer’s disease is characterized by extracellular (outside of cells) ‘amyloid plaques’ composed of deposits of protein called Aβ, and intracellular (within cells) ‘neurofibrillary tangles’ composed of a protein called tau. The molecular connection between Aβ and tau is still unclear.
Animal models have been used to try and better understand the role of tau in Alzheimer’s disease and other neurodegenerative diseases.1 Transgenic mice expressing tau have been developed to generate disease models for tauopathies. A mouse line expressing human genomic tau expresses all 6 brain isoforms of tau and allows study of human tau in vivo. Crossing tau transgenic mice with those that overproduce Aβ has created very useful models for Alzheimer’s disease. These models have provided important information on the relationship between tau and Aβ. Also, knock-out of endogenous mouse tau alleviates Aβ-induced memory deficits, which suggests that targeting tau may be a worthwhile Alzheimer’s disease therapy.
Normally, tau is involved in the assembly and stabilization of microtubules, a ‘cytoskeletal’ element within cells. Microtubules are critical for cellular function, especially in neurons. Too much tau may overly stabilize the microtubules and too little tau may destabilize microtubules. Tau knock-out mice (in which the tau gene has been inactivated2) display only mild phenotypes, such as muscle weakness, hyperactivity, and impaired fear conditioning. However, they do not exhibit neurodegeneration, which suggests that the neurodegeneration is not due to simple loss of tau function.
In 1998, the understanding of the role of aberrant tau in neurodegenerative disease was significantly advanced when mutations in the tau gene were discovered to be associated with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). The FTDP-17 mutations provide clear evidence that alterations in tau alone could cause neurodegenerative disease, and strongly suggest that aberrant tau plays a pathogenic role in Alzheimer’s disease and other taupathies (neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain). At least 37 mutations associated with FTDP-17T or related disorders have been identified.
- Wolfe MS. Tau mutations in neurodegenerative diseases. Journal of Biological Chemistry. 2009;284:6021-6025.
- National Human Genome Research Institute. Knock-out Mice Fact Sheet. https://www.genome.gov/12514551/knockout-mice-fact-sheet/knockout-mice-fact-sheet/ Accessed September 1, 2016.