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Apo E, Cholesterol Lowering Agents and HMG CoA Reductase in Sporadic Alzheimer's Disease

View Judes Poirier's presentation.

The discovery that the apolipoprotein E4 (apoE4) allele is strongly linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the 4 allele has been associated with lower levels of apoE in both serum and brain tissues in AD. Moreover, synaptic integrity and plasticity is markedly compromised in an 4 allele dose-dependent manner in several brain areas in AD. These observations led us to propose that the apoE4 allele compromises cholesterol and phospholipids transport in the CNS, and indirectly impair the synaptic integrity and plasticity by depriving neurons from its key membrane components. In an attempt to reverse the apoE deficit in E4 carriers, we identified and characterized several apoE inducer drugs from a low throughput astrocyte screening assays and developed one particularly strong apoE inducer drug called Probucol. The administration of this old cholesterol lowering drug in mild to moderate sporadic AD led to significant increases in CSF apoE levels, decrease CSF beta amyloid 1-42 and relative stabilization of the cognitive symptoms during 6 months.

While we initially focused on cholesterol transport modifications in AD, we also carefully examined cholesterol synthesis in the CNS. The majority of the autopsy-confirmed AD subjects that were examined in our study exhibit a 30%-85% loss of the Hydroxymethylglutaryl Coenzyme A Reductase (HMGR) activity in the frontal and temporal cortex without changes in total HMGR mRNA prevalence. However, nucleic acid sequencing analyses of the HMGR transcripts revealed the presence of multiple transcripts in the brain of AD subjects, including intron-retention and exon skipping versions of the normal mRNA. One abnormal HMGR transcript that contains intronic sequences inversely correlates with total beta amyloid concentration in our autopsy-confirmed AD cases. Abnormal HMGR proteins are also generated in the brain as a consequence of the mis-processing of the defective HMGR transcript. These results implicate that in addition to lipid transport mediated by apoE, cholesterol homeostasis in the brain of AD is markedly altered in response to alterations in the HMGR pathway; suggesting a possible explanation for the potentially beneficial effect of statins in common AD.

Supported by CIHR (JP, DC), Alcan (JP, MP), Astra Zeneca Corporation (JP), and the Alzheimer Society of Canada (JP).

*J. Poirier, M. Panisset, D. Dea, N. Aumont, D. Champagne and L. Lamarre-Théroux. Centre for Studies in Aging, Douglas Hospital Research Centre, Montreal, PQ, Canada H4H 1R3

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