Differential Regulation of Amyloid-β Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms

Abstract

Background: Apolipoprotein E (apoE) regulates amyloid-␤ (A␤) clearance in an isoform-dependent manner. Results: Internalized A␤ traffics to lysosomal and recycling pathways. ApoE3 more efficiently promotes A␤ lysosomal trafficking and degradation than apoE4. Conclusion: ApoE isoforms differentially affect A␤ lysosomal trafficking and degradation. Significance: Differential effects of apoE isoforms on A␤ cellular degradation may explain why apoE4 is a risk factor for Alzheimer disease.

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

“…Previous results have shown that the detergent and guanidine extraction pattern of mouse apoE parallels that of A␤42 in 5ϫFAD mice (5), and the proportion of apoE/A␤ in insoluble fractions was increased in AD synaptosomes compared with controls. 6 Importantly, insoluble apoE4/A␤ complex may accumulate in autophagic structures within synaptic terminals (66,67). However, the effect of APOE genotype on soluble synaptic apoE/A␤ levels is less clear.…”

Retinoic Acid Isomers Facilitate Apolipoprotein E Production and Lipidation in Astrocytes through the Retinoid X Receptor/Retinoic Acid Receptor Pathway

“…ApoE and A␤ bind to each other and also to their common receptors, including LRP1, LDLR, and heparan sulfate proteoglycan (11,12). Thus, apoE might compete with A␤ for receptor binding (67), although if it forms complexes with A␤, it might also facilitate cellular A␤ binding and uptake (28). Thus, the specific effects of apoE on A␤ clearance may be depending on their concentrations, apoE isoforms, apoE lipidation status, A␤ aggregation status, and specific cell types.…”

“…After washing two times with PBS, cells were dissolved in 5 M guanidine in 50 mM Tris-HCl (pH 8.0). To measure A␤42, samples were captured with mAb 2.1.3 followed by detection with HRP-conjugated Ab5 (28).…”

Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

“…Most internalized A␤ is delivered to the lysosomal pathway for degradation (32). We then studied whether synj1 reduction would affect the amount of Alexa Fig.…”

“…These results suggest that internalized A␤ 42 is transported more rapidly to the endosome/lysosome degradation pathway in neurons with synj1 reduction. 2 Levels-Furthermore, to assess lysosomal degradation of A␤, we tested the effects of lysosomal inhibitors (leupeptin, pepstatin A, and E-64d), which block lysosomal enzyme activities (32,33). N2a cells transfected with synj1 or control siRNA for 4 days were then incubated in the presence or absence of lysosomal inhibitors for 24 h. The amount of media and cell-associated A␤ in the presence of lysosomal inhibitors, determined by IP/Western blotting, were significantly increased (Fig.…”