Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

Amanda Hanna, Kayleigh Iremonger, Pritam Das, Dennis W Dickson, Todd Golde, Christopher Janus

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Introduction: The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Abeta) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Abeta plaque burden. Methods: Mice were tested at 3, 6, and 12 months of age, which corresponds to early, mild, and severe Abeta plaques deposition, following a cross-sectional experimental design. We used delay version of fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of training chamber. The Abeta plaque burden was evaluated at each age after the completion of the behavioral tests. Results: CRDN8 mice showed comparable to control mice context fear memory at 3 and 6 months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Abeta plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Conclusions: Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlate well with overall increase in Abeta burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.

Original languageEnglish (US)
Pages (from-to)21
Number of pages1
JournalAlzheimer's Research & Therapy
DOIs
StateAccepted/In press - Jun 14 2012

Fingerprint

Amyloid Plaques
Amyloidosis
Fear
Amyloid beta-Protein Precursor
Amygdala
Hippocampus
Alzheimer Disease
Limbic System
Entorhinal Cortex
Neurofibrillary Tangles
Memory Disorders
Amyloid
Transgenic Mice
Foot
Shock
Research Design
Genes

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Neurology
  • Clinical Neurology

Cite this

Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis. / Hanna, Amanda; Iremonger, Kayleigh; Das, Pritam; Dickson, Dennis W; Golde, Todd; Janus, Christopher.

In: Alzheimer's Research & Therapy, 14.06.2012, p. 21.

Research output: Contribution to journalArticle

@article{6705a4411383461494a9025ab7d714a8,
title = "Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis",
abstract = "Introduction: The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Abeta) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Abeta plaque burden. Methods: Mice were tested at 3, 6, and 12 months of age, which corresponds to early, mild, and severe Abeta plaques deposition, following a cross-sectional experimental design. We used delay version of fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of training chamber. The Abeta plaque burden was evaluated at each age after the completion of the behavioral tests. Results: CRDN8 mice showed comparable to control mice context fear memory at 3 and 6 months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Abeta plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Conclusions: Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlate well with overall increase in Abeta burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.",
author = "Amanda Hanna and Kayleigh Iremonger and Pritam Das and Dickson, {Dennis W} and Todd Golde and Christopher Janus",
year = "2012",
month = "6",
day = "14",
doi = "10.1186/alzrt124",
language = "English (US)",
pages = "21",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

AU - Hanna, Amanda

AU - Iremonger, Kayleigh

AU - Das, Pritam

AU - Dickson, Dennis W

AU - Golde, Todd

AU - Janus, Christopher

PY - 2012/6/14

Y1 - 2012/6/14

N2 - Introduction: The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Abeta) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Abeta plaque burden. Methods: Mice were tested at 3, 6, and 12 months of age, which corresponds to early, mild, and severe Abeta plaques deposition, following a cross-sectional experimental design. We used delay version of fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of training chamber. The Abeta plaque burden was evaluated at each age after the completion of the behavioral tests. Results: CRDN8 mice showed comparable to control mice context fear memory at 3 and 6 months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Abeta plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Conclusions: Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlate well with overall increase in Abeta burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.

AB - Introduction: The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Abeta) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Abeta plaque burden. Methods: Mice were tested at 3, 6, and 12 months of age, which corresponds to early, mild, and severe Abeta plaques deposition, following a cross-sectional experimental design. We used delay version of fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of training chamber. The Abeta plaque burden was evaluated at each age after the completion of the behavioral tests. Results: CRDN8 mice showed comparable to control mice context fear memory at 3 and 6 months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Abeta plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Conclusions: Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlate well with overall increase in Abeta burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.

UR - http://www.scopus.com/inward/record.url?scp=84862237175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862237175&partnerID=8YFLogxK

U2 - 10.1186/alzrt124

DO - 10.1186/alzrt124

M3 - Article

C2 - 22697412

AN - SCOPUS:84862237175

SP - 21

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

SN - 1758-9193

ER -