Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer's Disease

Kaan E Biron,Rayshad Gopaul,Wilfred A Jefferies,Dara L Dickstein,Maria G Castro

doi:10.1371/journal.pone.0023789

Abstract

Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder and is the leading cause of dementia in the elderly [1]
We report that the Tg2576 AD mice exhibit no apparent vascular apoptosis but have significant tight junction (TJ) disruption, which is directly related to neoangiogenesis leading to a significant increase in vascular density in AD brain
Leakiness in AD is likely due to vascular deterioration and apoptosis resulting from brain hypoxia

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder and is the leading cause of dementia in the elderly [1]. Genetic factors including the apolipoprotein E genotype and an associated polymorphism in the ATPbinding cassette A1 lipid transporter indicate a direct link between AD and vascular disease [12]. Approximately 90% of AD patients have cerebrovascular amyloid angiopathy (CAA), consisting of abeta in small arteries, arterioles and capillaries [13]. CAA involves the deposition of abeta within the small blood vessels of the brain and is found within the walls of the leptomeninges and parenchymal arteries, arterioles and capillaries [17,18]. The E22Q (Dutch), and E22G (Arctic) mutants produce vasculotropic variants peptides of abeta 1–40 that contribute distinct hereditary phenotypes of cerebral amyloid angiopathy, manifesting varying degrees of brain vessels tropism and cytotoxic effects, and impaired microvessel remodeling and angiogenesis [20] that differentially activate mitochondrial apoptotic pathways [21]

Objectives

Methods

Results

Conclusion