Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease.

Miles Frost,Abby Keable,Diana Andreea Zbarcea,Johannes Attems,Paul R Chiarot,Roy O Weller,Roxana O Carare,Matt Macgregor Sharp,Ho Ming Yuen,Maureen Gatherer,Dan Baseley,Amber Sealy,Colin Smith

doi:10.3390/ph13090261

Abstract

Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function may explain the deposition of amyloid-beta as cerebral amyloid angiopathy (CAA), a key feature of Alzheimer’s disease. The α-adrenoceptor subtype α1A is abundant in the brain, but its distribution in the cerebral vessels is unclear. We analysed cultured human cerebrovascular SMCs and young, old and CAA human brains for (a) the presence of α1A receptor and (b) the distribution of the α1A receptor within the cerebral vessels. The α1A receptor was present on the wall of cerebrovascular SMCs. No significant changes were observed in the vascular expression of the α1A-adrenergic receptor in young, old and CAA cases. The pattern of vascular staining appeared less punctate and more diffuse with ageing and CAA. Our results show that the α1A-adrenergic receptor is preserved in cerebral vessels with ageing and in CAA and is expressed on cerebrovascular smooth muscle cells, suggesting that vascular adrenergic receptors may hold potential for therapeutic targeting of IPAD.

Highlights

Alzheimer’s disease (AD) is the commonest form of dementia, and a key pathological feature of AD is represented by the accumulation of amyloid-beta (Aβ) within the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA) [1]
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This would be relevant to the accumulation of protein deposits in the vessel wall as CAA caused by a reduced efficiency of intramural periarterial drainage (IPAD), a process that most likely relies upon adrenergic innervation [13]

Summary

Introduction

Alzheimer’s disease (AD) is the commonest form of dementia, and a key pathological feature of AD is represented by the accumulation of amyloid-beta (Aβ) within the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA) [1]. Apart from the supply of blood, which decreases in early AD through hypoperfusion, the cerebral arteries have another recently recognized function: the drainage of waste and soluble interstitial fluid along their walls [5]. Lymphatic drainage of the brain occurs along the basement membranes of capillaries and arteries, as intramural periarterial drainage (IPAD) [7,8,9]. With increasing age and possession of ApoE ε4 genotype, vascular basement membranes change their composition, thereby reducing the efficiency of IPAD [10,11,12]

Methods

Results

Conclusion