Elsevier

Neuroscience

Volume 121, Issue 1, 26 September 2003, Pages 99-110
Neuroscience

The cholesterol-lowering drug Probucol increases apolipoprotein e production in the hippocampus of aged rats: implications for Alzheimer’s disease

https://doi.org/10.1016/S0306-4522(03)00361-0Get rights and content

Abstract

Several recent epidemiological studies have proposed that cholesterol-lowering drug Statin may provide protection against Alzheimer's disease (AD). Probucol is a non-Statin cholesterol-lowering drug and a potent inducer of apolipoprotein E (apoE) production in peripheral circulation. A recent clinical study using Probucol in elderly AD subjects revealed a concomitant stabilisation of cognitive symptoms and significant increases in apoE levels in the cerebral spinal fluid in these patients. To gain insight into the mechanisms underlying these effects, we treated a cohort of aged male rats (26-month-old) with oral dose of Probucol for 30 days.

Specifically, we examined the effects of Probucol on apoE production and its receptors (low density lipoprotein receptor [LDLr] and low density lipoprotein receptor-related protein [LRP]), astroglial marker of cell damage (glial fibrillary acidic protein [GFAP]), markers of neuronal synaptic plasticity and integrity (synaptosomal associated protein of 25 kDa [SNAP-25] and synaptophysin) as well as cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCoAr]) in the hippocampus. We report that Probucol induces the production of apoE and one of its main receptors, LRP, increases HMGCoAr (rate-limiting enzyme in cholesterol synthesis), substantially attenuates age-related increases in glial activation, and induces production of synaptic marker SNAP-25, a molecule commonly associated with synaptogenesis and dendritic remodeling.

These findings suggest that Probucol could promote neural and synaptic plasticity to counteract the synaptic deterioration associated with brain aging through an apoE/LRP-mediated system. Consistent with the beneficial effects of other cholesterol-lowering drugs such as the Statin, Probucol could also offers additional benefits based on apoE neurobiology.

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.

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