LDL Receptor Deficiency Does not Alter Brain Amyloid-β Levels but Causes an Exacerbation of Apoptosis
(2020) In Journal of Alzheimer's disease : JAD 73(2). p.585-596- Abstract
Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related... (More)
Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.
(Less)
- author
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- keywords
- Aging/metabolism, Amyloid beta-Protein Precursor/metabolism, Animals, Apoptosis/genetics, Brain Chemistry/genetics, Caspase 3, Cholesterol/blood, Gene Expression, Hippocampus/metabolism, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Prefrontal Cortex/metabolism, Receptors, LDL/deficiency
- in
- Journal of Alzheimer's disease : JAD
- volume
- 73
- issue
- 2
- pages
- 585 - 596
- publisher
- IOS Press
- external identifiers
-
- scopus:85078505647
- pmid:31815695
- ISSN
- 1387-2877
- DOI
- 10.3233/JAD-190742
- language
- English
- LU publication?
- no
- id
- 460fd37e-85e3-4f79-9efb-0d230f3121b4
- date added to LUP
- 2021-09-21 19:50:35
- date last changed
- 2024-06-16 19:17:14
@article{460fd37e-85e3-4f79-9efb-0d230f3121b4,
abstract = {{<p>Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.</p>}},
author = {{de Oliveira, Jade and Engel, Daiane F and de Paula, Gabriela C and Melo, Helen M and Lopes, Samantha C and Ribeiro, Camila T and Delanogare, Eslen and Moreira, José Claudio F and Gelain, Daniel P and Prediger, Rui D and Gabilan, Nelson H and Moreira, Eduardo Luiz G and Ferreira, Sergio T and de Bem, Andreza F}},
issn = {{1387-2877}},
keywords = {{Aging/metabolism; Amyloid beta-Protein Precursor/metabolism; Animals; Apoptosis/genetics; Brain Chemistry/genetics; Caspase 3; Cholesterol/blood; Gene Expression; Hippocampus/metabolism; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Prefrontal Cortex/metabolism; Receptors, LDL/deficiency}},
language = {{eng}},
number = {{2}},
pages = {{585--596}},
publisher = {{IOS Press}},
series = {{Journal of Alzheimer's disease : JAD}},
title = {{LDL Receptor Deficiency Does not Alter Brain Amyloid-β Levels but Causes an Exacerbation of Apoptosis}},
url = {{http://dx.doi.org/10.3233/JAD-190742}},
doi = {{10.3233/JAD-190742}},
volume = {{73}},
year = {{2020}},
}