. Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience. 2002 Jan;110(2):199-211.


Amyloid b(1-42), a major component of amyloid plaques, binds with exceptionally high affinity to the a 7 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 b(1-42). Consecutive section immunohistochemistry and digital imaging were used to reveal the spatial relationship between amyloid b(1-42) and the a 7 receptor in affected neurons of Alzheimer's disease brains. Results showed that neurons containing substantial intracellular accumulations of amyloid b(1-42) invariably express relatively high levels of the a 7 receptor. Furthermore, this receptor is highly co-localized with amyloid b(1-42) within neurons of Alzheimer's disease brains. To experimentally test the possibility that the binding interaction between exogenous amyloid b(1-42) and the a 7 receptor facilitates internalization and intracellular accumulation of amyloid b(1-42) in Alzheimer's disease brains, we studied the fate of exogenous amyloid b(1-42) and its interaction with the a 7 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 b(1-42), but not amyloid b(1-40). Furthermore, the rate and extent of amyloid b(1-42) internalization was related directly to the a 7 receptor protein level, since (1) the rate of amyloid b(1-42) accumulation was much lower in untransfected cells that express much lower levels of this receptor and (2) internalization was effectively blocked by a-bungarotoxin, an a 7 receptor antagonist. As in neurons of Alzheimer's disease brains, the a 7 receptor in transfected cells was precisely co-localized with amyloid b(1-42) in prominent intracellular aggregates. Internalization of amyloid b(1-42) in transfected cells was blocked by phenylarsine oxide, an inhibitor of endocytosis.We suggest that the intraneuronal accumulation of amyloid b(1-42) in Alzheimer's disease brains occurs predominantly in neurons that express the a 7 receptor. In addition, internalization of amyloid b(1-42) may be facilitated by the high-affinity binding of amyloid b(1-42) to the a 7 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 a 7 receptor in Alzheimer's disease brains and for the fact that amyloid b(1-42) is the dominant amyloid b peptide species in intracellular accumulations and amyloid plaques.


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