Lipid peroxidation and pathological disruption of the ApoE/Reelin-ApoER2-DAB1 axis in sporadic Alzheimer's disease

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.

LRP1 and SORL1 regulate tau internalization and degradation and enhance tau seeding

ABSTRACTThe identification of the apoE receptor, LRP1, as an endocytic receptor for tau raises several questions about LRP1s’ role in tauopathies. Is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation? Does LRP1 internalize pathological tau leading to cytosolic seeding? Do other, related receptors participate in these processes? We confirm that LRP1 rapidly internalizes tau, leading to efficient lysosomal degradation. Employing brain homogenates from human Alzheimer brain, we find that LRP1 also mediates cytosolic tau seeding. We additionally found that another apoE receptor, SORL1, a gene implicated in AD risk, also mediates tau endocytosis, degradation, and release into the cytoplasm of seed competent species. These data suggest a role for these apoE receptors in tau uptake, as well as the competing processes of degradation and release to the cytoplasm. The balance of these processes may be fundamental to spread of neuropathology across the brain in Alzheimer disease.

Reelin signaling antagonizes β-amyloid at the synapse

Abnormal processing of the amyloid precursor protein (APP) and β-amyloid (Aβ) plaque accumulation are defining features of Alzheimer disease (AD), a genetically complex neurodegenerative disease that is characterized by progressive synapse loss and neuronal cell death. Aβ induces synaptic dysfunction in part by altering the endocytosis and trafficking of AMPA and NMDA receptors. Reelin is a neuromodulator that increases glutamatergic neurotransmission by signaling through the postsynaptic ApoE receptors Apoer2 and Vldlr and thereby potently enhances synaptic plasticity. Here we show that Reelin can prevent the suppression of long-term potentiation and NMDA receptors, which is induced by levels of Aβ comparable to those present in an AD-afflicted brain. This reversal is dependent upon the activation of Src family tyrosine kinases. At high concentrations of Aβ peptides, Reelin can no longer overcome the Aβ induced functional suppression and this coincides with a complete blockade of the Reelin-dependent phosphorylation of NR2 subunits. We propose a model in which Aβ, Reelin, and ApoE receptors modulate neurotransmission and thus synaptic stability as opposing regulators of synaptic gain control.