Intracellular accumulation of β-amyloid1–42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer’s disease
Section snippets
Tissue samples
Post-mortem brain tissues (entorhinal cortex and hippocampus) from patients with clinically diagnosed sporadic AD (n=62, age range=72–78) and control tissues from normal, age-matched, neurologically normal (n=20, age range=69–76) individuals were obtained from the Harvard Brain Tissue Resource Center (HBTRC, Belmont, MA, USA) and Analytical Biological Services (Wilmington, DE, USA) and fixed in a 10% neutral buffered formalin solution. The HBTRC is supported in part by a Public Health Service
Aβ1–42 accumulates intracellularly in AD brains and is abundant in APs
Immunohistochemistry using three different Aβ42-specific antibodies revealed that APs were the most prominent Aβ42-positive feature in AD brains (Fig. 1A), but were generally lacking in most age-matched control brains (Fig. 1B). APs were also conspicuously absent from the molecular layer of the entorhinal cortex of AD brains, which contains primarily the dendritic trees of pyramidal neurons and is largely devoid of their associated perikarya (Fig. 1A). In addition to APs, Aβ42 was highly
Discussion
Recent work has suggested that Aβ42 first accumulates intracellularly, rather than extracellularly, and that pyramidal neurons are primary targets in the entorhinal cortex and hippocampus of AD brains (Gouras et al., 2000, D’Andrea et al., 2001). Furthermore, we have provided strong evidence that Aβ42-burdened cells eventually undergo lysis in AD brains and that each neuronal lysis event may correspond to the formation of a single AP (D’Andrea et al., 2001, Wang et al., 2001). Since pyramidal
Conclusions
Although binding of Aβ peptides to the α7nAChR may also alter calcium ion influx and acetylcholine release, our results point to an important role for the α7nAChR in facilitating the entry and intraneuronal accumulation of Aβ42 via endocytosis. Thus, the interaction of these two proteins may represent a key step in the pathogenesis of AD. This study demonstrates that the neuronal expression of the α7nAChR is strongly correlated with the rate and extent of Aβ42 accumulation. The high-affinity
Acknowledgements
The authors wish to thank Dr. Daniel H.S. Lee for the use of the transfected SK-N-MC cells. This work was supported in part by a grant from the National Institute on Aging (AG00925).
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