Microglia contribute to cognitive decline in hypercholesterolemic LDLr−/− mice

Author:

Rodrigues Matheus Scarpatto1ORCID,do Nascimento Natalia Baltazar1,Farias Hemelin Resende1,Schons Taina1,Machado Alessandra Gonçalves1,Behenck Eduarda2,Mesquita Ariadni1,Krolow Bast Rachel1,Budni Josiani2,Engblom David3,de Bem Andreza Fabro4ORCID,de Oliveira Jade1ORCID

Affiliation:

1. Programa de Pós‐Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS) Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre Brazil

2. Programa de Pós‐Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde Universidade do Extremo Sul Catarinense Criciúma Brazil

3. Center for Social and Affective Neuroscience (CSAN) Linköping University Linköping Sweden

4. Instituto de Ciências Biológicas Universidade de Brasília Brasília Brazil

Abstract

AbstractFamilial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low‐density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood–brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr−/−) mice. We noticed that microgliosis was more severe in the hippocampus of middle‐aged LDLr−/− mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr−/− mice already showed increased microgliosis and decreased immunocontent of claudin‐5 in the prefrontal cortex (PFC). Subsequently, 6‐month‐old male C57BL/6 wild‐type and LDLr−/− mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr−/− mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non‐treated LDLr−/− mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region‐specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6‐month‐old LDLr−/− mice exhibited a slight but not significant increase in IBA‐1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr−/− mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.image

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Biochemistry

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