Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy

Allan Wang, Pritam Das, Robert C. Switzer, Todd E. Golde, Joanna L. Jankowsky

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood- brain barrier, bound to plaques, and was still be found associated with a subset of amyloid depositsmanymonths after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.

Original languageEnglish (US)
Pages (from-to)4124-4136
Number of pages13
JournalJournal of Neuroscience
Volume31
Issue number11
DOIs
StatePublished - Mar 16 2011

Fingerprint

Amyloid
Immunotherapy
Alzheimer Disease
Passive Immunization
Doxycycline
Amyloid beta-Protein Precursor
Therapeutics
Blood-Brain Barrier
Phagocytosis
Transgenic Mice
Anti-Idiotypic Antibodies
Clinical Trials
Injections
Antibodies
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy. / Wang, Allan; Das, Pritam; Switzer, Robert C.; Golde, Todd E.; Jankowsky, Joanna L.

In: Journal of Neuroscience, Vol. 31, No. 11, 16.03.2011, p. 4124-4136.

Research output: Contribution to journalArticle

Wang, Allan ; Das, Pritam ; Switzer, Robert C. ; Golde, Todd E. ; Jankowsky, Joanna L. / Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 11. pp. 4124-4136.
@article{0405bdcc20c041ff839360185a89ba36,
title = "Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy",
abstract = "Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52{\%} and Aβ42 content by 28{\%} relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood- brain barrier, bound to plaques, and was still be found associated with a subset of amyloid depositsmanymonths after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.",
author = "Allan Wang and Pritam Das and Switzer, {Robert C.} and Golde, {Todd E.} and Jankowsky, {Joanna L.}",
year = "2011",
month = "3",
day = "16",
doi = "10.1523/JNEUROSCI.5077-10.2011",
language = "English (US)",
volume = "31",
pages = "4124--4136",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "11",

}

TY - JOUR

T1 - Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy

AU - Wang, Allan

AU - Das, Pritam

AU - Switzer, Robert C.

AU - Golde, Todd E.

AU - Jankowsky, Joanna L.

PY - 2011/3/16

Y1 - 2011/3/16

N2 - Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood- brain barrier, bound to plaques, and was still be found associated with a subset of amyloid depositsmanymonths after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.

AB - Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood- brain barrier, bound to plaques, and was still be found associated with a subset of amyloid depositsmanymonths after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.

UR - http://www.scopus.com/inward/record.url?scp=79952775194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952775194&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.5077-10.2011

DO - 10.1523/JNEUROSCI.5077-10.2011

M3 - Article

C2 - 21411653

AN - SCOPUS:79952775194

VL - 31

SP - 4124

EP - 4136

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 11

ER -