P2‐186: Hydroxynonenal generated crosslinking fluorophores accumulate in Alzheimer's disease

Lipid peroxidation generates reactive aldehydes, most notably hydroxynonenal (HNE), which covalently binds amino acid residue side chains leading to protein inactivation and insolubility. Specific adducts of lipid peroxidation have been demonstrated in intimate association with pathological lesions of Alzheimer disease (AD), suggesting that oxidative stress is a major component of Alzheimer disease pathogenesis. Recent studies have further demonstrated that some hydroxynonenal-protein products have physical and chemical properties similar to lipofuscin, providing a direct link between lipid peroxidation and the lipofuscin accumulation that commonly occurs in post-mitotic cells such as neurons. In this study we examine brain tissue from patients with Alzheimer disease and controls by immunocytochemistry and immunoelectron microscopy for evidence of HNE crosslinking modifications of the type that should accumulate in the lipofuscin pathway. While no immunolabeling of classical Alzheimer disease pathological lesions (neuritic plaques, neurofibrillary tangles) was detected, we noted strong labeling of granulovacuolar degeneration (GVD) and Hirano bodies but not lipofuscin. These findings directly implicate lipid crosslinking peroxidation products as accumulating not in the lesions or in the lipofuscin pathways but instead in a distinct pathway, GVD, that accumulates cytosolic proteins. Our findings also suggest, by virtue of Hirano body immunolabeling, that actin and actin-associated proteins accumulate hydroxynonenal crosslinking. These findings highlight a possible dichotomy of protein turnover in AD, where membrane bounded-organelles are degraded in lysosome/lipofuscin and cytosolic proteins degraded in an alternate pathway.