Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules

ABSTRACT Microtubule–associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical filaments in neurons

undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P–tau) in a nonsaturable fashion, forming large tangles of filaments 3.3 ±

0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P–tau alone, are made up of filaments several microns in length and are labeled with tau

antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD P–tau to aggregate with normal tau and prevents tangle formation. AD P–tau disassembles microtubules

assembled from normal tau and tubulin. These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the degeneration of

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REFERENCES * Tomlinson, B.E., Blessed, G. & Roth, M. Observations on the brains of demented old people. _J. Neurol. Sci._ 11, 205–242 (1970). Article  CAS  Google Scholar  * Alafuzoff,

I., Iqbal, K., Friden, H., Adolfsson, R. & Winblad, B. Histopathological criteria for progressive dementia disorders: Clinical-pathological correlation and classification by multivariate

data analysis. _Acta Neuropathol._ 74, 209–225 (1987). Article  CAS  Google Scholar  * Grundke-Iqbal, I. _et al_. Abnormal phosphorylation of the microtubule-associated protein tau in

Alzheimer cytoskeletal pathology. _Proc. Natl. Acad. Sci. USA_ 83, 4913–4917 (1986). Article  CAS  Google Scholar  * Grundke-Iqbal, I. _et al_. Microtubule-associated protein tau: A

component of Alzheimer paired helical filaments. _J. Biol. Chem._ 261, 6084–6089 (1986). CAS  PubMed  Google Scholar  * Köpke, E. _et al_. Microtubule associated protein tau: Abnormal

phosphorylation of non-paired helical filament pool in Alzheimer disease. _J. Biol. Chem._ 268, 24374–24384 (1993). PubMed  Google Scholar  * Khatoon, S., Grundke-Iqbal, I. & Iqbal, K.

Brain levels of microtubule associated protein tau are elevated in Alzheimer's disease brain: A radioimmunoslot-blot assay for nanograms of the protein. _J. Neurochem._ 59, 750–753

(1992). Article  CAS  Google Scholar  * Alonso, A.d.C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer

disease. _Proc. Natl. Acad. Sci. USA_ 91, 5562–5566 (1994). Article  CAS  Google Scholar  * Iqbal, K., Zaidi, T., Bancher, C. & Grundke-Iqbal, I. Alzheimer paired helical filaments:

Restoration of the biological activity by dephosphorylation. _FEBS Lett._ 349, 104–108 (1994). Article  CAS  Google Scholar  * Wang, J.-Z., Gong, C.-X., Zaidi, T., Grundke-Iqbal, I. &

Iqbal, K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and-2B. _J. Biol. Chem._ 270, 4854–4860 (1995). Article  CAS  Google Scholar  * Iqbal, K. _et al_.

Defective brain microtubule assembly in Alzheimer's disease. _Lancet_ 2, 421–426 (1986). Article  CAS  Google Scholar  * Ruben, G.C. _et al_. The microtubule associated protein tau

forms a triple stranded left-hand helical polymer. _J. Biol. Chem._ 266, 22019–22027 (1991). CAS  PubMed  Google Scholar  * Wang, J.-Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of

microtubule associated protein tau: An abnormal posttranslational modification in Alzheimer disease. _Nature Medicine_, see accompanying manuscript. * Ruben, G.C., Iqbal, K., Wisniewski,

H.M., Johnson, J.E., Jr. & Grundke-Iqbal, I. Alzheimer neurofibrillary tangles contain 2.1-nm filaments structurally identical to the microtubule associated protein tau: A high

resolution transmission electron microscope study of tangles and senile plaque core amyloid. _Brain Res._ 590, 164–179 (1992). Article  CAS  Google Scholar  * Wille, H., Drewes, G., Biernat,

J., Mandelkow, E.M. & Mandelkow, E. Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau _in vitro_ . _J. Cell Biol._ 118,

573–584 (1992). Article  CAS  Google Scholar  * Crowther, R.A., Olesen, O.F., Jakes, R. & Goedert, M. The microtubule binding repeats of tau protein assemble into filaments like those

found in Alzheimer's disease. _FEBS Lett._ 309, 199–202 (1992). Article  CAS  Google Scholar  * Crowther, R.A., Olesen, O.F., Smith, M., Jakes, R. & Goedert, M. Assembly of

Alzheimer-like filaments from full-length tau protein. _FEBS Lett._ 337, 135–138 (1994). Article  CAS  Google Scholar  * Schweers, O., Mandelkow, E.M., Biernat, J. & Mandelkow, E.

Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein τ controls the _in vitro_ assembly of paired helical filaments. _Proc. Natl. Acad. Sci. USA_ 92, 8463–8467

(1995). Article  CAS  Google Scholar  * Bancher, C. _et al_. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease.

_Brain Res._ 477, 90–99 (1989). Article  CAS  Google Scholar  * Gong, C.-X., Singh, T.J., Grundke-Iqbal, I. & Iqbal, K. Phosphoprotein phosphatase activities in Alzheimer disease brain.

_J. Neurochem._ 61, 921–927 (1993). Article  CAS  Google Scholar  * Gong, C.-X. _et al_. Phosphatase activity towards abnormally phosphorylated τ: Decrease in Alzheimer disease brain. _J.

Neurochem._ 65, 732–738,(1995). Article  CAS  Google Scholar  * Ruben, G.C., Harris, E.D. Jr. & Nagase, H. Electron microscope studies of free and proteinase-bound duck ovostatins

(ovomacroglobins): Model of ovostatin structure and its transformation upon proteolysis. _J. Biol. Chem._ 263, 2861–2869 (1988). CAS  PubMed  Google Scholar  * Wrzolek, M.A. _et al_. Immune

electron microscopic characterization of monoclonal antibodies to Alzheimer neurofibrillary tangles. _Am. J. Pathol._ 141, 343–355 (1992). CAS  PubMed  PubMed Central  Google Scholar  *

Grundke-Iqbal, I. _et al_. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. _Mol. Brain Res._ 4, 43–52 (1988). Article  CAS  Google Scholar  *

Alonso, A. del C., Grundke-Iqbal, I. & Iqbal, K. Bovine and human tau, highly homologous but less crossreactive: Implications for Alzheimer disease. _Brain Res._ 31, 194–200 (1995). CAS

  Google Scholar  * Bensadoun, A. & Weinstein, D. Assay of proteins in the presence of interfering materials. _Anal. Biochem._ 70, 241–250 (1976). Article  CAS  Google Scholar  *

Shelanski, M.L., Gaskin, F. & Cantor, C.R. Microtubule assembly in the absence of added nucleotides. _Proc. Natl. Acad. Sci. USA_ 70, 765–768 (1973). Article  CAS  Google Scholar  *

Sloboda, R.D. & Rosenbaum, J.L. Decoration and stabilization of intact, smooth-walled microtubules with microtubule-associated proteins. _Biochemistry_ 18, 48–55 (1979). Article  CAS 

Google Scholar  * Biernat, J. _et al_. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding

region. _EMBO J._ 11, 1593–1597 (1992). Article  CAS  Google Scholar  * Greenberg, S.G., Davies, P., Schein, J.D. & Binder, L. Hydrofluoric acid-treated τ. PHF proteins display the same

biochemical properties as normal τ. _J. Biol. Chem._ 267, 564–569 (1992). CAS  PubMed  Google Scholar  * Otvos, L. _et al_. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at

serine residue 396 and residue 404. _J. Neurosci. Res._ 39, 669–673 (1994). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION Author notes * Alejandra del C. Alonso

Present address: Departamento di Química Biólogica, Facultad de Cs. Qs. – U.N.C., Cuidad Universitaria – Pab. Argentina, cc 61 – cp 5016, Cordoba, Argentina AUTHORS AND AFFILIATIONS * New

York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, 10314, USA Alejandra del C. Alonso, Inge Grundke-Iqbal & Khalid

Iqbal * Departamento de Química Biológica, Facultad de Cs. Qs. - U.N.C., Ciudad Universitaria - Pab. Argentina, cc 61 - cp 5016, Cordoba, Argentina Alejandra del C. Alonso Authors *

Alejandra del C. Alonso View author publications You can also search for this author inPubMed Google Scholar * Inge Grundke-Iqbal View author publications You can also search for this author

inPubMed Google Scholar * Khalid Iqbal View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Alonso, A., Grundke-Iqbal, I. & Iqbal, K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles

microtubules. _Nat Med_ 2, 783–787 (1996). https://doi.org/10.1038/nm0796-783 Download citation * Received: 04 December 1995 * Accepted: 22 May 1996 * Published: 01 July 1996 * Issue Date:

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