FIGURE 11. Schematic of inferred relationships between oxidative lipid damage and amyloidogenesis.

Solid arrows represent chemical conversions; open arrows represent positive kinetic effects. In the absence of biochemical pathology, polyunsaturated fatty acyl chains (PUFA) and soluble unaggregated Aβ (Aβ_S) are present (the encircled species). Pathological cycles are entered when any type of oxidative damage causes lipid hydroperoxides to form. Lipid hydroperoxides decay spontaneously into HNE and other products, including isoprostanes. HNE and Aβ_S combine to form various HNE-modified Aβ (HNE-Aβ). These species promote the conversion of Aβ_S into fibrillar Aβ (Aβ_F). Aβ_S also forms a nonfibrillar intermediate species, Aβ_I, and binds Cu(II) ions. When Aβ-bound Cu(II) is reduced, Cu(I) leads to hydroxyl radical formation and promotes oxidative lipid damage (32). It is not known whether Aβ_I forms under the influence of external factors or if it is on path to the formation of Aβ_F from Aβ_S.