Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology.

The unique structural and biophysical features of apolipoprotein (apo) E4 - domain interaction and molten globule formation - have been correlated with the detrimental effects of apoE4 in neuropathology. Two examples of how the structure of apoE4 determines the pathological outcome in neurons include apoE4 potentiation of amyloid beta-induced lysosomal leakage and apoptosis and the proteolytic cleavage of apoE synthesized by neurons. Thus, a new therapeutic target is to identify small molecules to modulate the inherent neuropathological structure of apoE4, i.e. to prevent domain interaction and to convert apoE4 to an apoE3-like molecule. A second therapeutic target is to inhibit the apoE-cleaving enzyme. This would prevent the generation of the reactive carboxyl-terminal fragments of apoE that enter the cytosol, disrupt the cytoskeleton, and cause neurodegeneration. ApoE4 is more susceptible than apoE3 to proteolytic cleavage and is thus more likely to cause detrimental effects in the central nervous system. It is predictable that apoE4 acts through various pathways to cause cognitive decline and neurodegeneration.