Date Published: July 27, 2017
Publisher: BioMed Central
Author(s): Hoau-Yan Wang, Caryn Trocmé-Thibierge, Andres Stucky, Sanket M. Shah, Jessica Kvasic, Amber Khan, Philippe Morain, Isabelle Guignot, Eva Bouguen, Karine Deschet, Maria Pueyo, Elisabeth Mocaer, Pierre-Jean Ousset, Bruno Vellas, Vera Kiyasova.
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.
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.
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.
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.
The severity of neurodegeneration in Alzheimer’s disease (AD) correlates with the soluble amyloid beta (Aβ) level in the brain . Aβ binds selectively and with high affinity to neuronal α7 nicotinic acetylcholine receptors (α7nAChRs), leading to intraneuronal Aβ42 accumulation, tau phosphorylation, and cholinergic dysfunction [2–5]. Therefore, chronic perturbation of the α7nAChRs by Aβ may contribute to neuronal dysfunctions and neurodegeneration leading to the formation of Aβ-rich plaque and neurofibrillary pathologies, which may be reduced by treatments that disrupt the Aβ42-α7nAChR interaction. This hypothesis is supported by data showing that S 24795, an α7nAChR partial agonist, blocks the Aβ42-α7nAChR interaction, Aβ42 internalization into neuronal cells, and Aβ42-induced tau phosphorylation [4, 5]. The critical role of α7nAChR in the Aβ-driven AD pathogenesis and cognitive deficits is further substantiated by the report showing that deletion of the α7nAChR gene reduces cognitive deficits and synaptic pathology in a mouse model of AD . Despite evidence of increased Aβ42-α7nAChR complex levels in lymphocytes from AD subjects , it remains ambiguous whether an increased Aβ42-α7nAChR complex level in lymphocytes may be a reliable AD biomarker. It is also unknown whether an increase in Aβ42-α7nAChR complexes is related to the apolipoprotein E (APOE) genotype, especially the ε4 subclass that is regarded as a prominent genetic risk factor for AD .
The present study shows that apoE4 interacts with α7nAChRs via the apoE LDL receptor binding domain, apoE141–148, to increase Aβ42-α7nAChR association and Aβ42-elicited, α7nAChR-dependent tau phosphorylation. Plasma from APOE ε4 carriers increased Aβ42-α7nAChR complex levels in rat synaptosomes. The relevance of these in vitro and ex vivo results to AD pathogenesis is supported by higher abundance of Aβ42-α7-like nAChR complexes in AD and MCI lymphocytes, correlating with the APOE ε4 genotype in hetero- and homozygous APOE ε4 carriers. Underscoring the more rapid cognitive decline in APOE ε4 carriers, we present a novel mechanism through which apoE4 may facilitate the Aβ42-driven AD pathogenesis in both brain and peripheral cells. Conspicuously, plasma from all AD subjects (independent of APOE ε4 status) has a greater effect on promoting the Aβ42-α7nAChR association, and lymphocytes of AD subjects have more abundant Aβ42-α7-like nAChR complexes. These findings suggest that other factor(s) in addition to APOE ε4 may be present in AD. Neurotoxic apoE proteolytic products can be formed by neurons in APOE ε4 transgenic mice and in the brains and cerebrospinal fluid from AD patients, with the highest level found in APOE ε4 carriers [11, 27, 36–38]. Some synthetic apoE fragments are neurotoxic [12, 13]. Since the neurotoxic apoE fragments retain the LDL binding domain [36, 39], the increased Aβ42-α7nAChR interaction in AD may result from higher apoE toxic fragments that presumably increase with duration of disease, although their presence in the plasma of AD subjects is currently not known.
Our data obtained from well-matched pairs in the ROSAS cohorts suggests that increased lymphocyte Aβ42-α7nAChR-like complexes may be a potential biomarker for AD pathologies. Importantly, we show that apoE4 enhances the Aβ42-α7nAChR interaction through apoE141–148 to contribute to apoE4-driven, Aβ42-mediated neurodysfunction and pathologies. Therapeutic agents that prevent or disrupt the Aβ42-α7nAChR association should be considered as disease-modifying therapeutics for AD patients, including APOE ε4 carriers.