α7nAChRs co-localize with brain regions underlying cognition and memory, are expressed in various cell types, and are the regulators of the cholinergic anti-inflammatory pathway. Amyloid beta 1-42 (Aβ_1–42) binds with high affinity to the α7nAChRs, which facilitates internalization of Aβ_1–42. A unique feature of the α7nAChR is the presence in different copy number variations and orientation of CHRFAM7A that harbors exons 5-10 of CHRNA7 and 4 exons of the FAM7A.

To study the functional consequences of the presence of the CHRFAM7A, two iPSC lines (0 copy and 1 copy direct) were developed and Medial Ganglionic Eminence progenitors and neurons were generated. As readouts for genotype-phenotype correlation, α7nAChR synaptic transmission and Aβ_1–42 uptake were tested.

Synaptic transmission in the presence of CHRFAM7A demonstrated that PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose response of Aβ_1–42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aβ_1–42 uptake activated neuronal interleukin 1β and TNFα without activating the canonical inflammasome pathway. Preliminary data on potential mechanisms are discussed.