Background: The apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer's disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation.
Methods: Coimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aβ)42-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aβ42-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes.
Results: In an ex vivo study using rodent synaptosomes, apoE141-148 of the apoE promotes Aβ42-α7nAChR association and Aβ42-induced α7nAChR-dependent tau phosphorylation. In a single-blind study, we examined lymphocytes isolated from control subjects, patients with MCI and dementia due to AD with known APOE genotypes, sampled at two time points (1 year apart). APOE ε4 genotype was closely correlated with heightened Aβ42-α7nAChR complex levels and with blunted exogenous Aβ42 effects in lymphocytes derived from AD and MCI due to AD cases. Similarly, plasma from APOE ε4 carriers enhanced the Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes. The progression of cognitive decline in APOE ε4 carriers correlated with higher levels of Aβ42-α7nAChR complexes in lymphocytes and greater enhancement by their plasma of Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes.
Conclusions: Our data suggest that increased lymphocyte Aβ42-α7nAChR-like complexes may indicate the presence of AD pathology especially in APOE ε4 carriers. We show that apoE, especially apoE4, promotes Aβ42-α7nAChR interaction and Aβ42-induced α7nAChR-dependent tau phosphorylation via its apoE141-148 domain. These apoE-mediated effects may contribute to the APOE ε4-driven neurodysfunction and AD pathologies.
Keywords: Alzheimer’s disease; Apolipoprotein E; Biomarker; Lymphocyte; Mild cognitive impairment; Synaptosome; tau phosphorylation; α7 Nicotinic acetylcholine receptor; β-Amyloid.