Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease

doi:10.1016/0006-8993(93)90021-E

Brain Research

Volume 623, Issue 1, 24 September 1993, Pages 142-146

https://doi.org/10.1016/0006-8993(93)90021-E Get rights and content

Abstract

In cerebral amyloid angiopathy, the amyloid-β (Aβ) deposits lie primarily in thetunica media suggesting that smooth muscle cells play an important role in Aβ deposition. To define this role, we conducted an immunocytochemical study of brain tissue from cases of Alzheimer disease with extensive cerebral amyloid angiopathy and cerebral hemorrhage. Antibodies specific to recombinant β protein precursor (βPP) and synthetic peptides homologous to various βPP sequences from residue 18 to 689 of βPP₆₉₅ were used. Antibodies to actin, tropomyosin, α-actinin or desmin were used to label muscle cells. Antibodies to Aβ sequences intensely recognized the extracellular amyloid deposit. Antibodies raised against βPP sequences other than the Aβ domain recognized smooth muscle cells. βPP-immunoreactivity was reduced in regions of Aβ deposits, since no muscle cells were recognized by cytoskeletal markers or observed ultrastructurally. In order to assess why Aβ is deposited in thetunica media, we used biotin-labelled βPP to determine if βPP can be locally retained. We found βPP bound to thetunica media of vessels but not other brain elements. These findings suggest Aβ in blood vessels derives from degenerating βPP-containing smooth muscle cells.

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Similar to amyloid plaques, which are found at a low level in healthy elderly, mild forms of CAA often appear asymptomatic and seem to be associated with brain Aβ deposition in healthy and/or preclinical AD as well as in AD patients (Park et al., 2013; Yates et al., 2011, 2014). However, CAA may also lead to severe vascular pathologies including degeneration of smooth muscle cells and disruption of the blood-brain barrier (Itoh et al., 1993; Kawai et al., 1993; Vinters, 1987). CAA is a risk factor for cerebral hemorrhages ranging from silent microbleeds to stroke (Zhang-Nunes et al., 2006).
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With prevalence >80% in AD (Ellis et al., 1996; Esiri and Wilcock, 1986), CAA is strongly associated with cognitive impairment (Attems et al., 2007; Greenberg et al., 2004) and with the appearance of cerebral hemorrhages (Pezzini et al., 2009). In CAA-AD, amyloid-beta (Aβ) peptide plaques accumulate in and around blood vessels inducing the degeneration of endothelial and smooth muscle cells (Kawai et al., 1993). Several factors influence the deposition of Aβ in blood vessels, including vasculotropic Aβ mutations such as the Dutch mutation (Herzig et al., 2004) or the failure of Aβ-clearance and/or degradation mechanisms.
An association between semicarbazide-sensitive amine oxidase (SSAO) and cerebral amyloid angiopathy (CAA) related to Alzheimer's disease (AD) has been largely postulated. Increased SSAO activity and expression have been detected in cerebrovascular tissue and plasma of AD patients, colocalizing with cerebrovascular amyloid-beta (Aβ) deposits. As an enzyme, SSAO metabolizes primary amines generating hydrogen peroxide, ammonia, and aldehydes. The ability of these products to generate oxidative stress, to enhance the advanced glycation end-product generation, to promote the Aβ aggregation in vitro, and to induce apoptosis supports its role in CAA-related vascular pathology. However, whether the SSAO increase constitutes a cause or it is a consequence of the pathologic process has not been elucidated so far. To set up the nature of this relationship, vascular cell models expressing SSAO were treated with different Aβ forms, simulating the CAA conditions in vitro. It was found that the presence of the vasculotropic Dutch-mutated Aβ_1–40 increases (Aβ_1–40 D) the SSAO-dependent toxicity, which is accompanied by an increase of SSAO protein availability in endothelial cell membranes. In addition, SSAO enhances Aβ_1–40 D and Aβ_1–42 deposition on vascular cells by both activity-dependent and -independent mechanisms. Thus, we provide evidences indicating that Aβ itself could be one of the factors inducing SSAO increase in AD, enhancing its toxic effect, and inducing the vascular dysfunction and, in turn, that SSAO stimulates Aβ deposition on the vascular walls, thereby contributing to the CAA-AD progression. Therefore, molecules inhibiting SSAO could provide an alternative treatment for preventing/delaying the progress of CAA-AD–associated vasculopathy.
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Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease

Abstract

Med. Hypotheses

Brain Res.

J. Biol. Chem.

Neurosci. Lett.

J. Neurol. Sci.

J. Biol. Chem.

Lancet

Brain Res.

Heavy metal intensification of DAB-based HRP reaction product

J. Histochem. Cytochem.

Amyloid angiopathy in Alzheimer's disease

Can. J. Neurol. Sci.

Neuronal and microglial involvement in β-amyloid protein deposition in Alzheimer's disease

Am. J. Pathol.

Immunochemical demonstration of tropomyosin in the neurofibrillary pathology of Alzheimer's disease

Am. J. Pathol.

Hirano body filaments contain actin and actin-associated proteins

J. Neuropathol. Exp. Neurol.

Cerebrovascular amyloidosis with cerebral hemorrhage

J. Neurol.

Clinically diagnosed Alzheimer's disease: autopsy results in 150 cases

Ann. Neurol.