Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Anllely Fernandez; Md Rejaul Hoq; Grace I. Hallinan; Daoyi Li; Sakshibeedu R. Bharath; Frank S. Vago; Xiaoqi Zhang; Kadir A. Ozcan; Kathy L. Newell; Holly J. Garringer; Wen Jiang; Bernardino Ghetti; Ruben Vidal

doi:10.1038/s41594-024-01252-3

Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Anllely Fernandez, Md Rejaul Hoq, Grace I. Hallinan, Daoyi Li, Sakshibeedu R. Bharath, Frank S. Vago, Xiaoqi Zhang, Kadir A. Ozcan, Kathy L. Newell, Holly J. Garringer, Wen Jiang, Bernardino Ghetti, Ruben Vidal

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Abstract

Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ₄₀ filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ₄₂ filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

Original language	English (US)
Pages (from-to)	903-909
Number of pages	7
Journal	Nature Structural and Molecular Biology
Volume	31
Issue number	6
DOIs	https://doi.org/10.1038/s41594-024-01252-3
State	Published - Jun 2024

All Science Journal Classification (ASJC) codes

Structural Biology
Molecular Biology

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10.1038/s41594-024-01252-3

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title = "Cryo-EM structures of amyloid-β and tau filaments in Down syndrome",

abstract = "Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.",

author = "Anllely Fernandez and Hoq, {Md Rejaul} and Hallinan, {Grace I.} and Daoyi Li and Bharath, {Sakshibeedu R.} and Vago, {Frank S.} and Xiaoqi Zhang and Ozcan, {Kadir A.} and Newell, {Kathy L.} and Garringer, {Holly J.} and Wen Jiang and Bernardino Ghetti and Ruben Vidal",

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doi = "10.1038/s41594-024-01252-3",

language = "English (US)",

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AU - Fernandez, Anllely

AU - Hoq, Md Rejaul

AU - Hallinan, Grace I.

AU - Li, Daoyi

AU - Bharath, Sakshibeedu R.

AU - Vago, Frank S.

AU - Zhang, Xiaoqi

AU - Ozcan, Kadir A.

AU - Newell, Kathy L.

AU - Garringer, Holly J.

AU - Jiang, Wen

AU - Ghetti, Bernardino

AU - Vidal, Ruben

PY - 2024/6

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N2 - Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

AB - Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

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Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Abstract

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