Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy

Abby Keable,Kate Fenna,Ho Ming Yuen,David A Johnston,Neil R Smyth,Colin Smith,Rustam Al-Shahi Salman,Neshika Samarasekera,James A.R Nicoll,Johannes Attems,Rajesh N Kalaria,Roy O Weller,Roxana O Carare

doi:10.1016/j.bbadis.2015.08.024

Abstract

Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Highlights

Deposition of insoluble amyloid β (Aβ) within the extracellular spaces of the brain and the accumulation of hyperphosphorylated tau within neurons as neurofibrillary tangles are major features in the pathology of Alzheimer's disease [1]
No significant changes were observed in young, old and cerebral amyloid angiopathy (CAA) brains in the percentage area stained for the collagen IV and fibronectin in the gray or white matter (Fig. 1)
We identified a few distinct patterns of deposition of Aβ in the basement membranes: Fig. 3A provides a representation of the visible co-localization of Col IV with Aβ within the leptomeningeal artery wall

Summary

Introduction

Deposition of insoluble amyloid β (Aβ) within the extracellular spaces of the brain and the accumulation of hyperphosphorylated tau within neurons as neurofibrillary tangles are major features in the pathology of Alzheimer's disease [1]. Aβ is deposited in the brain with age in non-demented individuals in addition to those with AD, strongly suggesting that there is an age-related failure of elimination of Aβ from the brain [2,3,4,5,6]. In addition to plaques in the brain, Aβ is deposited in the walls of cerebral capillaries and arteries as cerebral amyloid angiopathy (CAA) with age and in AD. In late stages of CAA, the walls of cerebral arteries are completely.

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