LDL Receptor Deficiency Does not Alter Brain Amyloid-β Levels but Causes an Exacerbation of Apoptosis

Article type: Research Article

Authors: de Oliveira, Jade^{a; b; *} | Engel, Daiane F.^b | de Paula, Gabriela C.^b | Melo, Helen M.^c | Lopes, Samantha C.^d | Ribeiro, Camila T.^a | Delanogare, Eslen^e | Moreira, José Claudio F.^a | Gelain, Daniel P.^a | Prediger, Rui D.^d | Gabilan, Nelson H.^b | Moreira, Eduardo Luiz G.^e | Ferreira, Sergio T.^{c; f} | de Bem, Andreza F.^{b; g}

Affiliations: [a] Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil | [b] Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil | [c] Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil | [d] Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil | [e] Departamento de Ciências Fisiológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil | [f] Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil | [g] Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, Brasil

Correspondence: [*] Correspondence to: Jade de Oliveira, PhD, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. Tel.: +55 5133085546; E-mail: deoliveirajade10@gmail.com.

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 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.

Keywords: Familial hypercholesterolemia, LDLr^-/- mice, memory impairment, amyloid-β, apoptosis

DOI: 10.3233/JAD-190742

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 585-596, 2020