Robert E. Becker & Ezio Giacobini 
Alzheimer Disease [PDF ebook] 
Therapeutic Strategies

Since the apo E4 allele is a risk factor or susceptibility gene in late-onset familial and sporadic AD, the mechanism of disease expression may involve metabolic effects that are isoform specific. Isoform-specific interactions of apo E therefore become critical in the mechanism of AD pathogenesis. Detailed characterization of the binding of the apo E isoforms with proteins and peptides relevant to the pathology of the disease may be critical in understanding disease pathogenesis. These critical isoform-specific interactions of apo E may involve interactions with proteins and pep tides in the defining neuropathologic lesions of the disease, the neurofibrillary tangle and senile plaque. Other possible critical isoform-specific interactions include the mechanism of internalization, intracellular trafficking, and subsequent metabolism. In addition, differential post-translational modifications of apo E isoforms may determine differences in metabolism contributing to the pathogenesis of the disease. Oxidation of apo E may confer several isoform-specific, biochemically distinct properties. Since {3A peptide binds apo E in the lipoprotein binding domain of the protein and not in the receptor-binding domain, apo E could target bound {3A4 peptide to neurons via the LRP receptor. Internalization of the apo EI {3A peptide complex into the cell, by the same route as the apo E-containing lipoproteins, would result in incorporation into primary lysosomes and p H dependent dissociation. The demonstration of apo E in the cytoplasm of neurons, with isoform-specific interactions of apo E with the microtubule-binding protein tau demonstrated in vitro, suggest additional, testable hypotheses of disease pathogenesis.