Matthew Lin

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease that currently has no effective treatment. Abnormalities with tau protein have been one of the key identifiers of Alzheimer’s disease since the discovery of the disease in 1907.² These abnormalities in tau can aggregate and form tau seeds that self propagate and cause misfolding of normal functioning tau protein. Although tau seeding and aggregations have been implicated in many Alzheimer’s patients, research shows that accumulation of tau does not necessarily lead to a tauopathy. This indicates that tau seeds may have a normal physiological function that goes awry in pathological diseases such as Alzheimer’s.³

Objective: The purpose of this study was to explore the mechanisms of tau seed formation and their relationship to the development of tauopathies.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “tau seeds”, “tauopathies”, “tau filaments”, and “Alzheimer’s Disease”.

Results: The studies found that the various tauopathies can be categorized by tau isoforms and microtubule repeats. All of these tauopathies are characterized by a specific tau fold that then spreads in a prion-like manner that typically starts in a small number of cells in the brain.⁵ A higher Braak stage indicates the overall accumulation of neurofibrillary tangles that typically characterizes Alzheimer’s Disease.⁵ Tau seeding was found across a wide range of ages indicating that age does not necessarily predict the amount of seeding found.³ PolyA RNA may prove to be a target of future therapeutics as it is involved in the formation of tau seeds.⁶

Conclusions: Tau seed assemblies occur early long before Alzheimer’s Disease presents and could be an area of therapeutic target.⁵ RNA appears to be a trigger of tau seed and fibril formation and may prove to be another area of therapeutic target.⁶ Intermediate filaments formed while tau assembles appear to play a major role in the pathogenesis of tauopathies, such as Alzheimer’s Disease. Targeting the specific pathogenic filaments could prove to prevent the disease.⁷ The specific conformation of tau seeds characterizes the tauopathy that will occur. In Alzheimer’s, the disease has been shown to be a mixture of 3R+4R tau isoforms in its filaments, which is distinct to other tauopathies.⁸

Works Cited:

1. Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s Mo/ Neurodegener. 2020;15:40. doi:10.1186/s13024-020-00391-7
2. Lane CA, Hardy J, Schott Alzheimer’s disease. EurJ Neural. 2018;25(1):59-70. doi:10.1111/ene.13439
3. Lacroix MS, Artikis E, Hitt BD, et Tau seeding without tauopathy. J Biol Chem. 2024;300(1):105545. doi:10.1016/j.jbc.2023.105545
4. Twarowski B, Herbet Inflammatory Processes in Alzheimer’s Disease-Pathomechanism, Diagnosis and Treatment: A Review. Int J Mo/ Sci. 2023;24(7):6518. doi:10.3390/ijms24076518
5. Manca M, Standke HG, Browne DF, et Tau seeds occur before earliest Alzheimer’s changes and are prevalent across neurodegenerative diseases. Acta Neuropathol (Berl). 2023;146(1):31-50. doi:10.1007/s00401-023-02574-0
6. Zwierzchowski-Zarate AN, Mendoza-Oliva A, Kashmer OM, Collazo-Lopez JE, White CL, Diamond Ml. RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds. J Biol Chem. 2022;298(8):102132. doi:10.1016/j.jbc.2022.102132
7. Lovestam S, Li D, Wagstaff JL, et Disease-specific tau filaments assemble via polymorphic intermediates. Nature. 2024;625(7993):119-125. doi:10.1038/s41586-023-06788-w
8. Shi Y, Zhang W, Yang Y, et Structure-based Classification of Tauopathies. Nature. 2021;598(7880):359-363. doi:10.1038/s41586-021-03911-7