The strong genetic link between Apolipoprotein E (ApoE) and sporadic Alzheimer's disease (AD) and the marked increase in brain lipid peroxidation observed in early AD suggest that dysfunctional lipid metabolism plays a central role in AD pathogenesis. However, specific mechanisms and targets linking ApoE and lipid peroxidation to AD are not well-defined. Here we used a combination of biochemical experiments, single-marker immunohistochemistry (IHC), and multiplex-IHC to examine the hypothesis that synaptic ApoE receptors and their ligands ApoE and Reelin are susceptible to lipid peroxidation, and that downstream disruptions in ApoE delivery and Reelin-ApoE receptor signaling cascades contribute to the pathogenesis of sporadic AD. We found that (1) Lys and His-enriched sequences within the binding regions of ApoER2, ApoE, VLDLR and Reelin, and recombinant ApoER2, ApoE and Reelin proteins, are vulnerable to attack by aldehydic products of lipid peroxidation, generating lipid-protein adducts and acid-stable ApoE receptor-ligand complexes; (2) ApoER2, lipid peroxidation-modified ApoE, native ApoE, Reelin, and multiple downstream components of Reelin-ApoE receptor signaling cascades that govern synaptic integrity [including DAB1, Tyr232-phosphorylated DAB1, Tyr607-phosphorylated Phosphatidylinositol 3-kinase, Thr508-phosphorylated LIM kinase-1, Ser202/Thr205-phosphorylated Tau and Thr19-phosphorylated-PSD95] accumulate in the immediate vicinity of neuritic plaques and surrounding abnormal neurons, and (3) several of these ApoE/Reelin-ApoE receptor-DAB1 pathway markers positively correlate with Braak stage, Aβ plaque load, and antemortem cognitive impairment. ApoE/Reelin-ApoER2-DAB1 axis pathologies were especially prominent in the dendritic compartments of the molecular layer of the dentate gyrus, cornu ammonis and subiculum, regions that receive synaptic input from the entorhinal-hippocampal projections that underlie memory formation. Taken together, these observations point toward extensive derangements in the ApoE/Reelin-ApoE receptor-DAB1 axis and provide evidence supporting a new, working hypothesis wherein lipid peroxidation-induced adduction and crosslinking of ApoE receptors and ApoE are proximate molecular events that compromise synaptic integrity and contribute to the histopathological hallmarks and cognitive deficits that characterize sporadic AD in humans.
Lipid peroxidation and Alzheimer’s disease: Key role of Amyloid-β
