Age-Related Cognitive Decline in Hypercholesterolemic LDL Receptor Knockout Mice (LDLr^−/−): Evidence of Antioxidant Imbalance and Increased Acetylcholinesterase Activity in the Prefrontal Cortex

Article type: Research Article

Authors: Moreira, Eduardo Luiz Gasnhar^{a; c} | de Oliveira, Jade^b | Nunes, Jean Costa^{c; d} | Santos, Danúbia Bonfanti^b | Nunes, Fernanda Costa^d | Vieira, Daniella Serafim Couto^d | Ribeiro-do-Valle, Rosa Maria^a | Pamplona, Fabrício Alano^a | de Bem, Andreza Fabro^b | Farina, Marcelo^b | Walz, Roger^c | Prediger, Rui Daniel^{a; c; *}

Affiliations: [a] Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil | [b] Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil | [c] Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil | [d] Serviço de Anatomia Patológica, Hospital Universitário Polydoro Ernani de São Thiago (HU), Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

Correspondence: [*] Correspondence to: Rui Daniel S. Prediger, PhD, Departamento de Farmacologia, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, SC, Brazil. Tel.: +55 48 3721 9491; Fax: +55 48 3337 5479; E-mail: ruidsp@hotmail.com.

Abstract: There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density lipoprotein receptor-deficient mice (LDLr−/−). The current findings provide new evidence that aged LDLr−/− mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr−/− mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex.

Keywords: Acetylcholinesterase activity, aging, cognitive deficits, LDL receptor knockout mice (LDLr^−/−), oxidative stress

DOI: 10.3233/JAD-2012-120541

Journal: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 495-511, 2012