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Special Issue "Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editor

Dr. Cheryl Hawkes
Website
Guest Editor
Open University, Milton Keynes, UK
Interests: Cerebral amyloid angiopathy; Alzheimer’s disease; neurovascular unit; perivascular drainage

Special Issue Information

Dear Colleagues,

Cerebral amyloid angiopathy (CAA), which is characterized pathologically by the deposition of b-amyloid (Ab) in the walls of cerebral blood vessels, is increasingly gaining recognition for its role in stroke and Alzheimer’s disease (AD). Initially thought to be a relatively benign by-product, CAA is now known to induce cerebral haemorrhage and contribute directly to AD dementia. While post-mortem analysis is needed to confirm the presence of CAA, radiological and other biomarkers have significantly improved the diagnosis of CAA. Over the past few decades, preclinical and experimental models have generated significant new understanding of the role of the cerebrovasculature in the clearance of Ab from the brain. However, the exact mechanism(s) by which environmental and genetic factors contribute to the etiology of CAA remain unknown. Furthermore, there are currently no approved therapies for the specific treatment of CAA. This Special Issue will feature a selection of original research, review articles, and commentaries related to the current understanding of the molecular and cellular underpinnings of the etiology, diagnosis, and treatment of CAA.

Dr. Cheryl Hawkes
Guest Editor

Manuscript Submission Information

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Keywords

  • Alzheimer’s disease
  • Stroke
  • Cerebrovasculature
  • Animal
  • Radiology
  • Beta-amyloid
  • Clearance mechanisms
  • Risk factors
  • Diagnosis
  • Treatment

Published Papers (8 papers)

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Research

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Open AccessArticle
Longitudinal Cognitive Decline in a Novel Rodent Model of Cerebral Amyloid Angiopathy Type-1
Int. J. Mol. Sci. 2020, 21(7), 2348; https://doi.org/10.3390/ijms21072348 - 28 Mar 2020
Cited by 1
Abstract
Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by β-amyloid (Aβ) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer’s disease (AD). Familial forms of CAA result from mutations within the Aβ domain of [...] Read more.
Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by β-amyloid (Aβ) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer’s disease (AD). Familial forms of CAA result from mutations within the Aβ domain of the amyloid β precursor protein (AβPP). Numerous transgenic mouse models have been generated around expression of human AβPP mutants and used to study cerebral amyloid pathologies. While behavioral deficits have been observed in many AβPP transgenic mouse lines, relative to rats, mice are limited in behavioral expression within specific cognitive domains. Recently, we generated a novel rat model, rTg-DI, which expresses Dutch/Iowa familial CAA Aβ in brain, develops progressive and robust accumulation of cerebral microvascular fibrillar Aβ beginning at 3 months, and mimics many pathological features of the human disease. The novel rTg-DI model provides a unique opportunity to evaluate the severity and forms of cognitive deficits that develop over the emergence and progression of CAA pathology. Here, we present an in-depth, longitudinal study aimed to complete a comprehensive assessment detailing phenotypic disease expression through extensive and sophisticated operant testing. Cohorts of rTg-DI and wild-type (WT) rats underwent operant testing from 6 to 12 months of age. Non-operant behavior was assessed prior to operant training at 4 months and after completion of training at 12 months. By 6 months, rTg-DI animals demonstrated speed–accuracy tradeoffs that later manifested across multiple operant tasks. rTg-DI animals also demonstrated delayed reaction times beginning at 7 months. Although non-operant assessments at 4 and 12 months indicated comparable mobility and balance, rTg-DI showed evidence of slowed environmental interaction. Overall, this suggests a form of sensorimotor slowing is the likely core functional impairment in rTg-DI rats and reflects similar deficits observed in human CAA. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessArticle
The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy
Int. J. Mol. Sci. 2020, 21(4), 1225; https://doi.org/10.3390/ijms21041225 - 12 Feb 2020
Abstract
In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as [...] Read more.
In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessArticle
Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model
Int. J. Mol. Sci. 2020, 21(3), 843; https://doi.org/10.3390/ijms21030843 - 28 Jan 2020
Cited by 1
Abstract
Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer’s disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly [...] Read more.
Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer’s disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessArticle
Reduced Levels of Cerebrospinal Fluid/Plasma Aβ40 as an Early Biomarker for Cerebral Amyloid Angiopathy in RTg-DI Rats
Int. J. Mol. Sci. 2020, 21(1), 303; https://doi.org/10.3390/ijms21010303 - 01 Jan 2020
Cited by 1
Abstract
The accumulation of fibrillar amyloid β-protein (Aβ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer’s disease. Presently, the clinical diagnosis of [...] Read more.
The accumulation of fibrillar amyloid β-protein (Aβ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer’s disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aβ40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aβ40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aβ40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aβ40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aβ40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessArticle
Norvaline Restores the BBB Integrity in a Mouse Model of Alzheimer’s Disease
Int. J. Mol. Sci. 2019, 20(18), 4616; https://doi.org/10.3390/ijms20184616 - 18 Sep 2019
Cited by 3
Abstract
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy [...] Read more.
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy metabolism, and chronic oxidative stress. Likewise, the blood–brain barrier (BBB) dysfunction is suggested to be a cause and AD consequence. Accordingly, therapeutic targeting of the compromised BBB is a promising disease-modifying approach. We utilized a homozygous triple-transgenic mouse model of AD (3×Tg-AD) to assess the effects of L-norvaline on BBB integrity. We scrutinized the perivascular astrocytes and macrophages by measuring the immunopositive profiles in relation to the presence of β-amyloid and compare the results with those found in wild-type animals. Typically, 3×Tg-AD mice display astroglia cytoskeletal atrophy, associated with the deposition of β-amyloid in the endothelia, and declining nitric oxide synthase (NOS) levels. L-norvaline escalated NOS levels, then reduced rates of BBB permeability, amyloid angiopathy, microgliosis, and astrodegeneration, which suggests AD treatment agent efficacy. Moreover, results undergird the roles of astrodegeneration and microgliosis in AD-associated BBB dysfunction and progressive cognitive impairment. L-norvaline self-evidently interferes with AD pathogenesis and presents a potent remedy for angiopathies and neurodegenerative disorders intervention. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Review

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Open AccessReview
Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Int. J. Mol. Sci. 2020, 21(6), 1992; https://doi.org/10.3390/ijms21061992 - 14 Mar 2020
Cited by 1
Abstract
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease directly implicated in Alzheimer’s disease (AD) pathogenesis through amyloid-β (Aβ) deposition, which may cause the development and progression of dementia. Despite extensive studies to explore drugs targeting Aβ, clinical benefits have not been reported in [...] Read more.
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease directly implicated in Alzheimer’s disease (AD) pathogenesis through amyloid-β (Aβ) deposition, which may cause the development and progression of dementia. Despite extensive studies to explore drugs targeting Aβ, clinical benefits have not been reported in large clinical trials in AD patients or presymptomatic individuals at a risk for AD. However, recent studies on CAA and AD have provided novel insights regarding CAA- and AD-related pathogenesis. This work has revealed potential therapeutic targets, including Aβ drainage pathways, Aβ aggregation, oxidative stress, and neuroinflammation. The functional significance and therapeutic potential of bioactive molecules such as cilostazol and taxifolin have also become increasingly evident. Furthermore, recent epidemiological studies have demonstrated that serum levels of a soluble form of triggering receptor expressed on myeloid cells 2 (TREM2) may have clinical significance as a potential novel predictive biomarker for dementia incidence. This review summarizes recent advances in CAA and AD research with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for CAA and AD. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessReview
Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis
Int. J. Mol. Sci. 2020, 21(6), 1985; https://doi.org/10.3390/ijms21061985 - 14 Mar 2020
Cited by 2
Abstract
Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and [...] Read more.
Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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Open AccessReview
The Amyloid-Tau-Neuroinflammation Axis in the Context of Cerebral Amyloid Angiopathy
Int. J. Mol. Sci. 2019, 20(24), 6319; https://doi.org/10.3390/ijms20246319 - 14 Dec 2019
Cited by 3
Abstract
Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with the accumulation of Aβ, other types [...] Read more.
Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with the accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis has been associated with an active immune response and perivascular deposition of hyperphosphorylated tau. Despite the fact that in Alzheimer’s disease (AD) a major focus of research has been the understanding of the connection between parenchymal amyloid plaques, tau aggregates in the form of neurofibrillary tangles (NFTs), and immune activation, the contribution of tau and neuroinflammation to neurodegeneration associated with CAA remains understudied. In this review, we discussed the existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in AD and AD-related dementias, to the pathogenesis of CAA. The detailed understanding of the “amyloid-tau-neuroinflammation” axis in the context of CAA could open the opportunity to develop therapeutic interventions for dementias associated with CAA that are currently being proposed for AD and AD-related dementias. Full article
(This article belongs to the Special Issue Cerebral Amyloid Angiopathy: Causes, Diagnosis and Treatment)
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