Intracellular Accumulation of beta-amyloid(1-42) in Neurons Is Facilitated by the Alpha 7 Nicotinic Acetylcholine Receptor in Alzheimer's Disease

Neuroscience. 2002;110(2):199-211. doi: 10.1016/s0306-4522(01)00460-2.

Abstract

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

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Binding Sites / physiology
  • Cytoplasm / metabolism
  • Cytoplasm / pathology
  • Endocytosis
  • Entorhinal Cortex / metabolism*
  • Entorhinal Cortex / pathology
  • Entorhinal Cortex / physiopathology
  • Fluorescent Antibody Technique
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Plaque, Amyloid / metabolism*
  • Plaque, Amyloid / pathology
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Tumor Cells, Cultured
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Amyloid beta-Peptides
  • Chrna7 protein, human
  • Peptide Fragments
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-protein (1-42)