The apoE receptor apoER2 is involved in the maintenance of efficient synaptic plasticity.

ApoER2 is one of the major receptors for ApoE in the brain, and has been shown to be involved not only in lipoprotein endocytosis, as other members of the LDL receptor family of receptors, but also in various cellular functions such as signalling and cellular guidance. By using a model of synaptic plasticity in mice lacking none, one or two alleles of the apoER2 gene, we investigated the implication of such a receptor deficiency on the remodelling process. Our results indicate that animals lacking apoER2 express higher levels of brain APP, as well as both key amyloid peptides, while apoE levels are slightly lower. Following entorhinal cortex lesioning, apoE levels increase in the deafferented hippocampus, while a delay in the increase of APP was observed. Hippocampal amyloid levels are also increased in response to the lesion, and highly potentiated by the complete absence of apoER2 gene. The results suggest a significant role for apoER2 in signalling various proteins in response to massive deafferentation and may participate in maintaining efficient synaptic plasticity and dendritic remodelling.

A polymorphism in lipoprotein lipase affects the severity of Alzheimer's disease pathophysiology.

Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases.

Non-steroidal anti-inflammatory drugs mediate increased in vitro glial expression of apolipoprotein E protein.

Epidemiological studies have shown that use of non-steroidal anti-inflammatory drugs (NSAIDs) by the elderly is associated with a decreased relative risk and a delayed onset of Alzheimer's disease (AD). In contrast, the apolipoprotein E (apoE) gene has proven to be a risk factor for AD with apoE epsilon 4 AD patients having been found to show lower levels of brain apoE. In the present study, treatment of primary rat mixed glial cell cultures with the common NSAIDs, indomethacin and aspirin, induced significant increases in extracellular apoE protein levels. Similarly, treatment of primary rat astrocyte cell cultures with aspirin and a cyclooxygenase (COX)-2-selective aspirin derivative also stimulated significant increases in apoE protein. However, astrocyte and mixed glial apoE protein levels were significantly reduced following exposure to COX-2-specific indomethacin amides and an inactive indomethacin derivative. ApoE protein modulation was observed at physiological and subphysiological concentrations well below the COX inhibition IC50 values of the NSAIDs used, suggestive of a COX-independent mechanism. In contrast to these results, indomethacin and aspirin treatment failed to induce any significant changes in apoE mRNA levels. The failure of NSAIDs to significantly alter apoE expression may have been indicative of a nontranscriptional mechanism of apoE protein induction. Consequently, NSAID-induced increases in apoE protein may enhance apoE-mediated immunosuppression and compensatory synaptic plasticity, potentially resulting in decreased AD risk and delay of disease onset.