A novel <i>AβPP</i> mutation exclusively associated with cerebral amyloid angiopathy

Obici, Laura; Demarchi, Andrea; Rosa, Giulia de; Bellotti, Vittorio; Marciano, Sabrina; Donadei, Simona; Arbustini, Eloisa; Palladini, Giovanni; Diegoli, Marta; Genovese, Egidio; Ferrari, Giancarlo V. De; Coverlizza, S.; Merlini, Giampaolo

doi:10.1002/ana.20571

Cited by 83 publications

(51 citation statements)

References 18 publications

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“…A new intra-A␤ mutation manifesting with comparable, albeit less aggressive features, has been found in Piedmont, Italy. The mutation, resulting from the substitution of Leu by Val at position 34 (A␤L34V), is also associated with severe CAA and fatal ICH, with amyloid deposition selectively affecting the cerebral vessel walls in the absence of parenchymal plaques (20).…”

mentioning

confidence: 99%

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

Hernández-Guillamón

Mawhirt

Fossati

et al. 2010

Journal of Biological Chemistry

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Patients carrying mutations within the amyloid-␤ (A␤) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with A␤ synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (A␤E22Q and A␤L34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the A␤ peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of A␤-(1-16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuteriumlabeled internal standards. Silencing MMP-2 gene expression resulted in reduced A␤ degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the A␤ peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of A␤E22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades A␤ species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype. Cerebral amyloid angiopathy (CAA)3 , the deposition of amyloid in vessel walls of the central nervous system, compromises leptomeningeal and cortical vessels affecting medium and small size arteries and arterioles as well as capillary endothelium. The most common form of CAA is associated with amyloid-␤ (A␤) deposition, particularly in elderly individuals and in patients with Alzheimer disease (AD) (1, 2). In these cases the deposited protein, A␤, is originated by sequential processing of the amyloid precursor protein primarily generating peptides constituted by 40-and 42-amino acid residue-long peptides, A␤40 and A␤42, respectively. For reasons not completely understood, A␤42 is one of the main components of parenchymal amyloid plaques, whereas A␤40 is the predominant species present in vascular deposits (2-4). The fibrillar and compact A␤ deposition in the brain vessel walls has been related to abnormalities in the vasculature including microaneurysms and fibrinoid necrosis (5), which can subsequently compromise the integrity of the blood brain barrier (BBB). Indeed, one of the most relevant pathological consequences of CAA is the development of intracerebral hemorrhages (ICH) usually affecting cortical and subcortical areas. In turn, ICH results in elevated mortality rates a...

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mentioning

confidence: 99%

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

Hernández-Guillamón

Mawhirt

Fossati

et al. 2010

Journal of Biological Chemistry

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“…In contrast, mutations that are associated with an increase in total Ab also have prominent Ab deposition in cerebral vessels (CAA) and can be clinically associated with cerebral hemorrhages and stroke (Kumar-Singh et al 2002;Castellani et al 2004). Although both CAA and senile plaques are observed in the brains of patients with DS, HCHWA-D, and AD, mutations within the Ab sequence are predominantly vasculotropic and lack neurofibrillary tangles (Obici et al 2005;Bugiani et al 2010). These mutations are also associated with more severe CAA, which is widely distributed throughout the brain (van Duinen et al 1987;Hendriks et al 1992;Rossi et al 2004;RoveletLecrux et al 2006).…”

Section: Mutations In the C-terminal Ab Domain And Their Effects On Amentioning

confidence: 99%

Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease

Tcw

Goate

2016

Cold Spring Harb Perspect Med

142

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Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of b-amyloid (Ab), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Ab is generated by proteolytic processing of the b-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of APP, leading to elevated APP expression, increased Ab deposition, and characteristic AD neuropathology. Sequencing of APP in familial early-onset AD identified missense mutations that cause AD, while a recently discovered coding variant, APP A673T, reduces the risk for AD. Cellular and animal studies show that risk-associated mutations increase total Ab levels, Ab42 levels, or Ab fibrillogenesis, while protective alleles reduce Ab levels. Together, these studies provide compelling evidence for the Ab hypothesis and suggest that therapeutics that reduces Ab levels or Ab fibrillogenesis should lower the risk for or prevent AD.

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“…Not surprisingly, with the involvement of Aβ CAA is the most common vascular comorbidity found in the brains of AD patients [36–38]. In addition to the prominent CAA that is present in AD and in spontaneous cases of this condition, several monogenic, familial forms of CAA exist that result from specific mutations that reside primarily within the middle region of the Aβ peptide sequence of AβPP gene [39–44] (Fig. 1).…”

Section: 2 Cerebral Amyloid Angiopathymentioning

confidence: 99%

“…Individuals afflicted with the Flemish-type A21G, Italian-type E22K and Piedmont-type L34V familial CAA are also prone to develop recurrent hemorrhagic strokes, cognitive decline and dementia [41,42,44]. In contrast, hemorrhages are more rare in the Arctic-type E22G disorder although this form is accompanied by enhanced Aβ protofibril formation and abundant parenchymal amyloid pathology [52,53].…”

Section: 2 Cerebral Amyloid Angiopathymentioning

confidence: 99%

The influence of the amyloid ß-protein and its precursor in modulating cerebral hemostasis

Nostrand

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Ischemic and hemorrhagic strokes are a significant cause of brain injury leading to vascular cognitive impairment and dementia (VCID). These deleterious events largely result from disruption of cerebral hemostasis, a well-controlled and delicate balance between thrombotic and fibrinolytic pathways in cerebral blood vessels and surrounding brain tissue. Ischemia and hemorrhage are both commonly associated with cerebrovascular deposition of amyloid β-protein (Aβ). In this regard, Aβ directly and indirectly modulates cerebral thrombosis and fibrinolysis. Further, major isoforms of the Aβ precursor protein (AβPP) function as a potent inhibitor of pro-thrombotic proteinases. The purpose of this review article is to summarize recent research on how cerebral vascular Aβ and AβPP influence cerebral hemostasis.

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A novel AβPP mutation exclusively associated with cerebral amyloid angiopathy

Cited by 83 publications

References 18 publications

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease

The influence of the amyloid ß-protein and its precursor in modulating cerebral hemostasis

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