Reversible memory loss in a mouse transgenic model of Alzheimer's disease

Linda A. Kotilinek, Brian Bacskai, Marcus Westerman, Takeshi Kawarabayashi, Linda Younkin, Bradley T. Hyman, Steven Younkin, Karen H. Ashe

Research output: Contribution to journalArticle

369 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Aβ, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Aβ and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Aβ disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Aβ. The beneficial effect of BAM-10 was not associated with a significant Aβ reduction, but instead eliminated the inverse relationship between brain Aβ and memory. We postulate that BAM-10 acts by neutralizing Aβ assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Aβ assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

Original languageEnglish (US)
Pages (from-to)6331-6335
Number of pages5
JournalJournal of Neuroscience
Volume22
Issue number15
StatePublished - Aug 1 2002

Fingerprint

Memory Disorders
Transgenic Mice
Alzheimer Disease
Cognition
Brain
Neurofibrillary Tangles
Amyloid beta-Protein Precursor
Amyloid Plaques
Monoclonal Antibodies
Peptides

Keywords

  • Alzheimer's disease
  • Behavior
  • Memory
  • Monoclonal antibodies
  • Transgenic

Cite this

Kotilinek, L. A., Bacskai, B., Westerman, M., Kawarabayashi, T., Younkin, L., Hyman, B. T., ... Ashe, K. H. (2002). Reversible memory loss in a mouse transgenic model of Alzheimer's disease. Journal of Neuroscience, 22(15), 6331-6335.

Reversible memory loss in a mouse transgenic model of Alzheimer's disease. / Kotilinek, Linda A.; Bacskai, Brian; Westerman, Marcus; Kawarabayashi, Takeshi; Younkin, Linda; Hyman, Bradley T.; Younkin, Steven; Ashe, Karen H.

In: Journal of Neuroscience, Vol. 22, No. 15, 01.08.2002, p. 6331-6335.

Research output: Contribution to journalArticle

Kotilinek, LA, Bacskai, B, Westerman, M, Kawarabayashi, T, Younkin, L, Hyman, BT, Younkin, S & Ashe, KH 2002, 'Reversible memory loss in a mouse transgenic model of Alzheimer's disease', Journal of Neuroscience, vol. 22, no. 15, pp. 6331-6335.
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT et al. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. Journal of Neuroscience. 2002 Aug 1;22(15):6331-6335.
Kotilinek, Linda A. ; Bacskai, Brian ; Westerman, Marcus ; Kawarabayashi, Takeshi ; Younkin, Linda ; Hyman, Bradley T. ; Younkin, Steven ; Ashe, Karen H. / Reversible memory loss in a mouse transgenic model of Alzheimer's disease. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 15. pp. 6331-6335.
@article{be032bbb20cc424aa606ac0ec18d0f1f,
title = "Reversible memory loss in a mouse transgenic model of Alzheimer's disease",
abstract = "Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Aβ, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Aβ and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Aβ disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Aβ. The beneficial effect of BAM-10 was not associated with a significant Aβ reduction, but instead eliminated the inverse relationship between brain Aβ and memory. We postulate that BAM-10 acts by neutralizing Aβ assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Aβ assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.",
keywords = "Alzheimer's disease, Aβ, Behavior, Memory, Monoclonal antibodies, Transgenic",
author = "Kotilinek, {Linda A.} and Brian Bacskai and Marcus Westerman and Takeshi Kawarabayashi and Linda Younkin and Hyman, {Bradley T.} and Steven Younkin and Ashe, {Karen H.}",
year = "2002",
month = "8",
day = "1",
language = "English (US)",
volume = "22",
pages = "6331--6335",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "15",

}

TY - JOUR

T1 - Reversible memory loss in a mouse transgenic model of Alzheimer's disease

AU - Kotilinek, Linda A.

AU - Bacskai, Brian

AU - Westerman, Marcus

AU - Kawarabayashi, Takeshi

AU - Younkin, Linda

AU - Hyman, Bradley T.

AU - Younkin, Steven

AU - Ashe, Karen H.

PY - 2002/8/1

Y1 - 2002/8/1

N2 - Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Aβ, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Aβ and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Aβ disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Aβ. The beneficial effect of BAM-10 was not associated with a significant Aβ reduction, but instead eliminated the inverse relationship between brain Aβ and memory. We postulate that BAM-10 acts by neutralizing Aβ assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Aβ assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

AB - Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Aβ, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Aβ and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Aβ disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Aβ. The beneficial effect of BAM-10 was not associated with a significant Aβ reduction, but instead eliminated the inverse relationship between brain Aβ and memory. We postulate that BAM-10 acts by neutralizing Aβ assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Aβ assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

KW - Alzheimer's disease

KW - Aβ

KW - Behavior

KW - Memory

KW - Monoclonal antibodies

KW - Transgenic

UR - http://www.scopus.com/inward/record.url?scp=0036703483&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036703483&partnerID=8YFLogxK

M3 - Article

C2 - 12151510

AN - SCOPUS:0036703483

VL - 22

SP - 6331

EP - 6335

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 15

ER -