Alpha7 nicotinic acetylcholine receptor expression by vascular smooth muscle cells facilitates the deposition of Abeta peptides and promotes cerebrovascular amyloid angiopathy.
Deposition of beta-amyloid (Abeta) peptides in the walls of brain blood vessels, cerebral amyloid angiopathy (CAA), is common in patients with Alzheimer's disease (AD). Previous studies have demonstrated Abeta peptide deposition among vascular smooth muscle cells (VSMCs), but the source of the Abeta and basis for its selective deposition in VSMCs are unknown. In the present study, we examined the deposition patterns of Abeta peptides, Abeta40 and Abeta42, within the cerebrovasculature of AD and control patients using single- and double-label immunohistochemistry. Abeta40 and Abeta42 were abundant in VSMCs, especially in leptomeningeal arteries and their initial cortical branches; in later-stage AD brains this pattern extended into the microvasculature. Abeta peptide deposition was linked to loss of VSMC viability. Perivascular leak clouds of Abeta-positive material were associated primarily with arterioles. By contrast, control brains possessed far fewer Abeta42- and Abeta40-immunopositive blood vessels, with perivascular leak clouds of Abeta-immunopositive material rarely observed. We also demonstrate that VSMCs in brain blood vessels express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which has high binding affinity for Abeta peptides, especially Abeta42. These results suggest that the blood and blood-brain barrier permeability provide a major source of the Abeta peptides that gradually deposit in brain VSMCs, and the presence and abundance of the alpha7nAChR on VSMCs may facilitate the selective accumulation of Abeta peptides in these cells.
Clifford
Peter M
PM
University of Medicine and Dentistry of New Jersey/Graduate School of Biomedical Sciences, 2 Medical Center Drive, Stratford, NJ 08084, USA.
Siu
Gilbert
G
Kosciuk
Mary
M
Levin
Eli C
EC
Venkataraman
Venkateswar
V
D'Andrea
Michael R
MR
Nagele
Robert G
RG
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000502:physiology; D002470:Cell Survival; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism* / Q000473:pathology; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor