Accumulating evidence suggests that cholesterol and cholesterol related proteins are involved in the pathogenesis of AD in humans and AD mouse models. Although the LDLR has been shown to have a major role in cholesterol and ApoE homeostasis in the periphery its role in the CNS remains unclear. Some LDLR polymorphisms showed a sex-dependent increased risk for developing AD in humans. In LDLR deficient mice, lack of LDLR increases brain ApoE but has no effect on hippocampal or CSF cholesterol. A number of studies using AD mice have provided evidence that the family of proteins involved in cholesterol metabolism as the ABCA1, the ApoA1, the SR-BI and the LDLR are involved in the pathogenesis of the AD-like phenotype in the mouse brain. Previous studies using different AD mouse models that were LDLR deficient resulted in conflicting data on the effect of LDLR deficiency on the amyloid related phenotype of the mice. Lack of LDLR had no effect on amyloid deposition in the brain in a study using a huAPP transgenic mouse while an analogous study using another huAPP transgenic mouse showed a significant increase in amyloid deposition. A recent study where LDLR was overexpressed in the brains of APP transgenic mice resulted in a significant decrease of amyloid plaque formation, thus establishing an important role for LDLR in the amyloid related pathology in the mouse brain. ApoE is a major risk factor in the pathogenesis of AD in the human population. We speculate that the type and position of the alteration may not noticeably interfere with the kinase domain structure. Alternatively, this polymorphism may be balanced by second-site mutations. For example, an altered site may have a biologically relevant negative effect on SUB conformation. However, it is conceivable that a second-site mutation in for example, a direct interactor of SUB may result in a protein that can still interact with the altered SUB protein and thus compensate for the principally deleterious effect. It is presently unclear if, and how often, this possibility actually occurs in the case of SUB in wild-type accessions. A different scenario, where accumulation of genetic incompatibilities between accessions can lead to reproductive isolation, has been described for SRF3. Genome sequencing has led to the discovery of myriads of new open reading frames from microbial, plant and animal systems whose cellular and biochemical functions are often unknown. Analysis of such proteins generally involves their expression in heterologous hosts, followed by their purification and biochemical characterization.