The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation.
We acknowledge Biochemical society for funding forBF. YA acknowledges Mustansiriyah University,Baghdad, Iraq (www.uomustansiriyah.edu.iq), for sup-port. We thank Pascale Schellenberger for valuablehelp and training with TEM. The human tissue wasprovided by the London Neurodegenerative DiseasesBrain Bank. Respectfully, we thank the anonymoustissue donors and their next of kin. We thank fundingfrom the BBSRC (BB/S003312/1, WFX and LCS) andthe EPSRC (EP/R513246/1, LL).Author contributionsYA managed the project, conceived the idea and pre-pared the samples. YA and BF collected and analysedthe TEM data; LB provided training and sectioned thebrain sample; YA, LL and WFX collected the AFMdata; and LL and WFX analysed the AFM data. JERprepared the purified dGAE protein. YA, BF and LSwrote the first draft and all authors reviewed themanuscript and approved the final version. CH, CWand LS managed the overall project.
AD brain tissue was provided by the London Neu-rodegenerative Diseases Brain Bank, Institute of Psy-chiatry, King’s College, London, under Local EthicsCommittee guidelines, and informed consent for braindonation was obtained from the next of kin by theLondon Neurodegenerative Diseases Brain Bank.
- Alzheimer’s disease
- neurofibrillary tangles
- paired helical filaments