de Oliveira_2014_J.Alzheimers.Dis_41_43

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 beta-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-beta-(Abeta)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Abeta(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Abeta 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 Abeta treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with Abeta(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Abeta(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Abeta-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment.