title: Increased susceptibility to amyloid-β-induced neurotoxicity in mice lacking the low-density lipoprotein receptor.
abstract: Familial hypercholesterolemia is caused by inherited genetic abnormalities that directly or indirectly affect the function of the low-density lipoprotein (LDL) receptor. This condition is characterized by defective catabolism of LDL which results in increased plasma cholesterol concentrations and premature coronary artery disease. Nevertheless, there is increasing preclinical and clinical evidence indicating that familial hypercholesterolemia subjects show a particularly high incidence of mild cognitive impairment. Moreover, the LDL receptor (LDLr) has been implicated as the main central nervous system apolipoprotein E receptor that regulates amyloid deposition in distinct mouse models of β-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-β-(Aβ)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Aβ(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Aβ toxicity, we observed oxidative stress, neuroinflammation, and neuronal membrane damage within the hippocampus of C57BL/6 wild-type mice, which were associated with spatial reference memory and working memory impairments. In addition, our data show that LDLr knockout (LDLr(-/-)) mice, regardless of Aβ treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with Aβ(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Aβ(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Aβ-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment.
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Jade
authors.initials: J
authors.lastname: de Oliveira
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Eduardo Luiz Gasnhar
authors.initials: EL
authors.lastname: Moreira
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Danúbia Bonfanti
authors.initials: DB
authors.lastname: dos Santos
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Tetsadê Camboim
authors.initials: TC
authors.lastname: Piermartiri
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, SC, Brazil.
authors.forename: Rafael Cypriano
authors.initials: RC
authors.lastname: Dutra
authors.affiliation: Universidade Federal do Pampa, Uruguaiana, RS, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Carla Inês
authors.initials: CI
authors.lastname: Tasca
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Rui Daniel Schröder
authors.initials: RD
authors.lastname: Prediger
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides; D000686:Amyloidosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D011973:Receptors, LDL; C078592:amyloid beta-protein (1-40); D013482:Superoxide Dismutase; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; LDL receptor; amyloid-β peptide; hypercholesterolemia; learning and memory; oxidative stress