Intracellular accumulation of β-amyloid_1-42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer's disease

Amyloid β_1-42, a major component of amyloid plaques, binds with exceptionally high affinity to the α7 nicotinic acetylcholine receptor and accumulates intracellularly in neurons of Alzheimer's disease brains. In this study, we investigated the possibility that this binding plays a key role in facilitating intraneuronal accumulation of amyloid β_1-42. Consecutive section immunohistochemistry and digital imaging were used to reveal the spatial relationship between amyloid β_1-42 and the α7 receptor in affected neurons of Alzheimer's disease brains. Results showed that neurons containing substantial intracellular accumulations of amyloid β_1-42 invariably express relatively high levels of the α7 receptor. Furthermore, this receptor is highly co-localized with amyloid β_1-42 within neurons of Alzheimer's disease brains. To experimentally test the possibility that the binding interaction between exogenous amyloid β_1-42 and the α7 receptor facilitates internalization and intracellular accumulation of amyloid β_1-42 in Alzheimer's disease brains, we studied the fate of exogenous amyloid β_1-42 and its interaction with the α7 receptor in vitro using cultured, transfected neuroblastoma cells that express elevated levels of this receptor. Transfected cells exhibited rapid binding, internalization and accumulation of exogenous amyloid β_1-42, but not amyloid β_1-40. Furthermore, the rate and extent of amyloid β_1-42 internalization was related directly to the α7 receptor protein level, since (1) the rate of amyloid β_1-42 accumulation was much lower in untransfected cells that express much lower levels of this receptor and (2) internalization was effectively blocked by α-bungarotoxin, an α7 receptor antagonist. As in neurons of Alzheimer's disease brains, the α7 receptor in transfected cells was precisely co-localized with amyloid β_1-42 in prominent intracellular aggregates. Internalization of amyloid β_1-42 in transfected cells was blocked by phenylarsine oxide, an inhibitor of endocytosis. We suggest that the intraneuronal accumulation of amyloid β_1-42 in Alzheimer's disease brains occurs predominantly in neurons that express the α7 receptor. In addition, internalization of amyloid β_1-42 may be facilitated by the high-affinity binding of amyloid β_1-42 to the α7 receptor on neuronal cell surfaces, followed by endocytosis of the resulting complex. This provides a plausible explanation for the selective vulnerability of neurons expressing the α7 receptor in Alzheimer's disease brains and for the fact that amyloid β_1-42 is the dominant amyloid β peptide species in intracellular accumulations and amyloid plaques.