The cholesterol-lowering drug Probucol increases apolipoprotein e production in the hippocampus of aged rats: implications for Alzheimer’s disease
Section snippets
Animals and Probucol administration
Males Long-Evans rats were purchased from Charles River, St-Constant, Quebec, Canada. All animals were housed two per cage, had ad libitum access to food and water, and were maintained on a 12-h light/dark cycle (lights on at 7:00 a.m.) with conditions of constant humidity and temperature (22 °C). Twenty-six-month-old rats (total n=28; average weight=550 g) were used. Probucol was dissolved in chloroform and was evenly sprayed on standard rat chow (Aburatani et al., 1988). Chloroform was
Body weight
Before the beginning of the experiment, rats were randomly allocated to either the control (n=14) or Probucol (n=14) groups, balancing the groups according to body weight. Body weight measurements were collected at the beginning and the end of the experiment. No significant differences were observed between body weight measurements taken at the beginning (672.73±35.06 versus 700.0±28.09) and the end (594.09±27.80 versus 618.33±28.67) of the experiment for control and Probucol-treated animals,
Discussion
The results of the present study show that chronic oral Probucol administration is associated with significant increases in hippocampal apoE levels. The increase is paralleled by an increase in the LRP protein concentration and HMGCoAr levels (rate-limiting enzyme in cholesterol synthesis). These effects were accompanied by a corresponding increase in synaptic marker SNAP-25, and concomitant reduction of astroglial marker GFAP. These results are consistent with a proof-of-principle study that
Conclusion
In the present study, we report that Probucol, a well-known cholesterol-lowering drug that does not belong to the Statin family, is capable of inducing the production of apoE and its receptor LRP, increase HMGCoAr (perhaps reflecting cholesterol de novo synthesis in discrete compartment of the astrocytes and/or neurons), substantially attenuates age-related increases in astroglial activation, and induces the expression of synaptic markers normally associated with synaptogenesis and dentritic
Acknowledgements
This work was supported by the Canadian Institute of Health Research (CIHR), the Alzheimer Society of Canada, and Alcan Corporation. D. Champagne is the recipient of CIHR Doctoral Award, J. Rochford is supported by a Chercheur Boursier (senior) award from the Fonds pour la Recherche en Sante du Quebec, and J. Poirier is supported by a Scientist Award from CIHR. We also wish to thank the J. A. Bombardier and the Birk Foundation for their support.
References (107)
- et al.
Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent
Brain Res
(1999) - et al.
The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease
Brain Res Brain Res Rev
(1998) - et al.
Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease
Brain Res Mol Brain Res
(1995) Discrepencies between the outcome of animals and human studies on the mode of action of probucol
Atherosclerosis
(1986)- et al.
Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase
J Biol Chem
(1978) - et al.
Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central nervous system
J Biol Chem
(1994) - et al.
3-Hydroxy-3-methylglutaryl coenzyme A reductase, cleavage, and condensing enzymes in relation to cholesterol formation in rat liver
Biochim Biophys Acta
(1960) - et al.
Clinical relevance of the quantification of apolipoprotein E in cerebrospinal fluid
Clin Chim Acta
(1991) - et al.
Reversal of presynaptic deficits of apolipoprotein E-deficient mice in human apolipoprotein E transgenic mice
Neuroscience
(2000) - et al.
Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury
Neuroscience
(1997)
Gonadal steroids regulate the expression of glial fibrillary acidic protein in the adult male rat hippocampus
Neuroscience
Comparison of effects of probucol versus vitamin on ex vivo oxidation susceptibility of lipoproteins in hyperlipoproteinemia
Am J Med
Glial fibrillary acidic protein (GFAP)the major protein of glial intermediate filaments in differentiated astrocytes
J Neuroimmunol
Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein
J Biol Chem
Gonadal hormones down-regulate reactive gliosis and astrocytic proliferation after penetrating brain injury
Brain Res
A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eucaryotes
J Biol Chem
Genotype-related differences of hippocampal apolipoprotein E levels only in early stages of neuropathological changes in Alzheimer's disease
Neuroscience
An immunohistochemical quantification of fibrous astrocytes in the aging human cerebral cortex
Neurobiol Aging
The LDL receptor gene family(un)expected signal transducers in the brain
Neuron
Effects of probucol on plasma lipoprotein subfractions and activities of lipoprotein lipase and hepatic triglyceride lipase
Atherosclerosis
Expression and distribution of the low density lipoprotein receptor-related mRNA in the rat central nervous system
Brain Res Mol Brain Res
Statins and the risk of dementia
Lancet
The effects of age, apolipoprotein E phenotype and gender on the concentration of amyloid-beta (A beta) 40, A beta 42, apolipoprotein E and transthyretin in human cerebrospinal fluid
Clin Biochem
Apolipoprotein E and apolipoprotein E receptors modulate AB-induced glial neuroinflammatory responses
Neurochem Int
Apolipoprotein E suppresses glial cell secretion of TNF alpha
J Neuroimmunol
Relevance of the quantification of apolipoprotein E in the cerebrospinal fluid in Alzheimer's
Neurosci Lett
Allelic discrimination using fluorogenic probes and the 5′-nuclease assay
Gen Anal Biomol Eng
Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response
J Neuroimmunol
Neurodegeneration in the central nervous system of apoE-deficient mice
Exp Neurol
The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction
Neuroscience
Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductasemevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme
J Biol Chem
Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein
Brain Res
Food restriction delays the age-related increase in GFAP mRNA in rat hypothalamus
Neurobiol Aging
Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease
Trends Neurosci
Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats
Neuroscience
Apolipoprotein E polymorphism and Alzheimer's disease
Lancet
Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning
Brain Res Mol Brain Res
Measurment of mRNA by quantitative PCR with a nonradioactive label
J Lipid Res
Oxidative insults are associated with apolipoprotein E genotype in Alzheimer's disease brain
Neurobiol Dis
Decline in reactive fiber growth in the dentate gyrus of aged rats compared to young adult rats following entorhinal cortex removal
Brain Res
Quantitative reverse transcription-polymerase chain reaction to study mRNA decaycomparison of endpoint and real-time methods
Anal Biochem
Influence of probucol on early experimental atherogenesis in hypercholesterolemic rats
Atherosclerosis
Neurotransmissionharnessing fusion machinery at the synapse
Trends Neurosci
Cerebrospinal fluid apoE and apoA-I concentrations in early- and late-onset Alzheimer's disease
Neurosci Lett
Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro
Exp Neurol
Effects of age on gene expression during estrogen-induced synaptic sprouting in the female rat
Exp Neurol
Mode of action of probucol in reducing serum cholesterol in mice
Jpn J Pharmacol
Increased levels of messenger ribonucleic acid for apolipoprotein E in the spleen of probucol-treated rabbits
Am J Cardiol
Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein E4 allele
J Neurosci
Cited by (59)
Alzheimer’s Disease Pharmacology
2022, Comprehensive PharmacologyThe interplay between lipid and Aβ amyloid homeostasis in Alzheimer's Disease: risk factors and therapeutic opportunities
2021, Chemistry and Physics of LipidsAPOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches
2021, The Lancet NeurologyRegulatory factor X1 depresses ApoE-dependent Aβ uptake by miRNA-124 in microglial response to oxidative stress
2017, NeuroscienceCitation Excerpt :Analyses of Aβ deposition in ApoE-knockout mice or human ε2, ε3 or ε4 knock-in mice cross-bread with APP transgenic mice showed that the reduction of Aβ deposition was ε2 > ε3 > ε4 and indicated that the influence of ApoE on Aβ metabolism also occurred in early steps prior to Aβ deposition (Fagan et al., 2002). Irrespective of ApoE isoforms, an inverse correlation between ApoE expression level and Aβ deposition was observed in LOAD cases (Landen et al., 1996; Champagne et al., 2003; Lambert et al., 2005), which indicates that the decrease in ApoE expression may be involved in the development of AD. However, the mechanism of reduced expression of ApoE is still unclear.
Design and Rationale for a Cognitive Outcome Substudy in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage
2016, Journal of Stroke and Cerebrovascular DiseasesNrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases
2016, Pharmacology and Therapeutics