Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice

Dongfeng Cao; Ken ichiro Fukuchi; Hongquan Wan; Helen Kim; Ling Li

doi:10.1016/j.neurobiolaging.2005.09.011

Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice

Dongfeng Cao, Ken ichiro Fukuchi, Hongquan Wan, Helen Kim, Ling Li

Experimental and Clinical Pharmacology

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

83 Scopus citations

Abstract

Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral β-amyloidosis. Before the manifestation of amyloid-β (Aβ) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Aβ deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-β precursor protein transgene, there was a significant increase in Aβ deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.

Original language	English (US)
Pages (from-to)	1632-1643
Number of pages	12
Journal	Neurobiology of Aging
Volume	27
Issue number	11
DOIs	https://doi.org/10.1016/j.neurobiolaging.2005.09.011
State	Published - Nov 2006

Bibliographical note

Funding Information:
We thank Dr. Karen Hsiao Ashe at University of Minnesota for providing parental Tg2576 mice. We also thank Dr. Robert Lalonde at University of Rouen in France for helpful discussion on the assessment of behavioral functions, Dr. Renee Desmond at UAB for her assistance in statistical analyses, and Dr. Paul Sanders at UAB for his careful reading of our manuscript. This study is supported in part by the Alzheimer's Association grants to L.L. (NIRG-00-2281) and to K.F. (ZEN-03-5834), the American Heart Association grant to L.L. (0455304B), the Center for Aging of UAB pilot grant to L.L., and the NIH grants to K.F. (NS43947) and to L.L. (AG025949).

Keywords

Amyloid deposition
Behavioral assessment
LDL receptor
Learning and memory
Transgenic mouse model

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10.1016/j.neurobiolaging.2005.09.011

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title = "Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice",

abstract = "Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral β-amyloidosis. Before the manifestation of amyloid-β (Aβ) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Aβ deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-β precursor protein transgene, there was a significant increase in Aβ deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.",

keywords = "Amyloid deposition, Behavioral assessment, LDL receptor, Learning and memory, Transgenic mouse model",

author = "Dongfeng Cao and Fukuchi, {Ken ichiro} and Hongquan Wan and Helen Kim and Ling Li",

note = "Funding Information: We thank Dr. Karen Hsiao Ashe at University of Minnesota for providing parental Tg2576 mice. We also thank Dr. Robert Lalonde at University of Rouen in France for helpful discussion on the assessment of behavioral functions, Dr. Renee Desmond at UAB for her assistance in statistical analyses, and Dr. Paul Sanders at UAB for his careful reading of our manuscript. This study is supported in part by the Alzheimer's Association grants to L.L. (NIRG-00-2281) and to K.F. (ZEN-03-5834), the American Heart Association grant to L.L. (0455304B), the Center for Aging of UAB pilot grant to L.L., and the NIH grants to K.F. (NS43947) and to L.L. (AG025949).",

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doi = "10.1016/j.neurobiolaging.2005.09.011",

language = "English (US)",

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journal = "Neurobiology of Aging",

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AU - Cao, Dongfeng

AU - Fukuchi, Ken ichiro

AU - Wan, Hongquan

AU - Kim, Helen

AU - Li, Ling

N1 - Funding Information: We thank Dr. Karen Hsiao Ashe at University of Minnesota for providing parental Tg2576 mice. We also thank Dr. Robert Lalonde at University of Rouen in France for helpful discussion on the assessment of behavioral functions, Dr. Renee Desmond at UAB for her assistance in statistical analyses, and Dr. Paul Sanders at UAB for his careful reading of our manuscript. This study is supported in part by the Alzheimer's Association grants to L.L. (NIRG-00-2281) and to K.F. (ZEN-03-5834), the American Heart Association grant to L.L. (0455304B), the Center for Aging of UAB pilot grant to L.L., and the NIH grants to K.F. (NS43947) and to L.L. (AG025949).

PY - 2006/11

Y1 - 2006/11

N2 - Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral β-amyloidosis. Before the manifestation of amyloid-β (Aβ) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Aβ deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-β precursor protein transgene, there was a significant increase in Aβ deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.

AB - Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral β-amyloidosis. Before the manifestation of amyloid-β (Aβ) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Aβ deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-β precursor protein transgene, there was a significant increase in Aβ deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.

KW - Amyloid deposition

KW - Behavioral assessment

KW - LDL receptor

KW - Learning and memory

KW - Transgenic mouse model

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JO - Neurobiology of Aging

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IS - 11

ER -

Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice

Abstract

Bibliographical note

Keywords

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