Aβ solubility and deposition during AD progression and in APP × PS-1 knock-in mice

M. Paul Murphy; Tina L. Beckett; Qunxing Ding; Ela Patel; William R. Markesbery; Daret K. St Clair; Harry LeVine; Jeffrey N. Keller

doi:10.1016/j.nbd.2007.06.002

Aβ solubility and deposition during AD progression and in APP × PS-1 knock-in mice

M. Paul Murphy, Tina L. Beckett, Qunxing Ding, Ela Patel, William R. Markesbery, Daret K. St Clair, Harry LeVine, Jeffrey N. Keller

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-β peptide (Aβ) is believed to be a possible substrate for AD, but little is currently known about Aβ alterations in MCI and how these changes compare to later stages of disease. In the present study Aβ was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APP × PS-1 knock-in mice were processed in parallel. We observed that Aβ₄₂ was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Aβ. Relative Aβ solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Aβ levels and solubility in a knock-in mouse model of Aβ pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinct changes in Aβ occur throughout the progression of AD, and that elevations in Aβ₄₂ occur at an early, clinically defined stage.

Original language	English
Pages (from-to)	301-311
Number of pages	11
Journal	Neurobiology of Disease
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.nbd.2007.06.002
State	Published - Sep 2007

Bibliographical note

Funding Information:
This work was supported by grants from the NIA (AG05119) (W.R.M., D.K.S., J.N.K.), NINDS (J.N.K.), NCRR (RR020171, M.P.M.), Alzheimer’s Association (J.N. K), R.C. Durr Endowed Chair for Alzheimer’s Research (J.N.K.), and the Abercrombie Foundation. The authors thank Ms. Paula Thomason and Sonya Anderson for technical assistance, and thank the participants of the Biologically Resilient Adults in Neurological Studies program, without whom these studies could not have been possible. The studies also thank Cephalon, Inc. and Dr Dorothy Flood for providing the initial breeding pairs of mice.

Keywords

Alzheimer's disease
Amyloid precursor protein
Amyloid-β peptide
Animal model
Mild cognitive impairment
Neuritic plaque

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2007.06.002

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@article{85a8432ba6b74ffc8511e3667d58d9be,

title = "Aβ solubility and deposition during AD progression and in APP × PS-1 knock-in mice",

abstract = "Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-β peptide (Aβ) is believed to be a possible substrate for AD, but little is currently known about Aβ alterations in MCI and how these changes compare to later stages of disease. In the present study Aβ was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APP × PS-1 knock-in mice were processed in parallel. We observed that Aβ42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Aβ. Relative Aβ solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Aβ levels and solubility in a knock-in mouse model of Aβ pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinct changes in Aβ occur throughout the progression of AD, and that elevations in Aβ42 occur at an early, clinically defined stage.",

keywords = "Alzheimer's disease, Amyloid precursor protein, Amyloid-β peptide, Animal model, Mild cognitive impairment, Neuritic plaque",

author = "Murphy, {M. Paul} and Beckett, {Tina L.} and Qunxing Ding and Ela Patel and Markesbery, {William R.} and {St Clair}, {Daret K.} and Harry LeVine and Keller, {Jeffrey N.}",

note = "Funding Information: This work was supported by grants from the NIA (AG05119) (W.R.M., D.K.S., J.N.K.), NINDS (J.N.K.), NCRR (RR020171, M.P.M.), Alzheimer{\textquoteright}s Association (J.N. K), R.C. Durr Endowed Chair for Alzheimer{\textquoteright}s Research (J.N.K.), and the Abercrombie Foundation. The authors thank Ms. Paula Thomason and Sonya Anderson for technical assistance, and thank the participants of the Biologically Resilient Adults in Neurological Studies program, without whom these studies could not have been possible. The studies also thank Cephalon, Inc. and Dr Dorothy Flood for providing the initial breeding pairs of mice. ",

year = "2007",

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doi = "10.1016/j.nbd.2007.06.002",

language = "English",

volume = "27",

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AU - Murphy, M. Paul

AU - Beckett, Tina L.

AU - Ding, Qunxing

AU - Patel, Ela

AU - Markesbery, William R.

AU - St Clair, Daret K.

AU - LeVine, Harry

AU - Keller, Jeffrey N.

N1 - Funding Information: This work was supported by grants from the NIA (AG05119) (W.R.M., D.K.S., J.N.K.), NINDS (J.N.K.), NCRR (RR020171, M.P.M.), Alzheimer’s Association (J.N. K), R.C. Durr Endowed Chair for Alzheimer’s Research (J.N.K.), and the Abercrombie Foundation. The authors thank Ms. Paula Thomason and Sonya Anderson for technical assistance, and thank the participants of the Biologically Resilient Adults in Neurological Studies program, without whom these studies could not have been possible. The studies also thank Cephalon, Inc. and Dr Dorothy Flood for providing the initial breeding pairs of mice.

PY - 2007/9

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N2 - Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-β peptide (Aβ) is believed to be a possible substrate for AD, but little is currently known about Aβ alterations in MCI and how these changes compare to later stages of disease. In the present study Aβ was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APP × PS-1 knock-in mice were processed in parallel. We observed that Aβ42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Aβ. Relative Aβ solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Aβ levels and solubility in a knock-in mouse model of Aβ pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinct changes in Aβ occur throughout the progression of AD, and that elevations in Aβ42 occur at an early, clinically defined stage.

AB - Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-β peptide (Aβ) is believed to be a possible substrate for AD, but little is currently known about Aβ alterations in MCI and how these changes compare to later stages of disease. In the present study Aβ was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APP × PS-1 knock-in mice were processed in parallel. We observed that Aβ42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Aβ. Relative Aβ solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Aβ levels and solubility in a knock-in mouse model of Aβ pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinct changes in Aβ occur throughout the progression of AD, and that elevations in Aβ42 occur at an early, clinically defined stage.

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KW - Neuritic plaque

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JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - 3

ER -

Aβ solubility and deposition during AD progression and in APP × PS-1 knock-in mice

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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