TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis

Weiss, Ronen; Lifshitz, Veronica; Frenkel, Dan

doi:10.1016/j.bbi.2010.11.012

Cited by 28 publications

(21 citation statements)

References 49 publications

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“…Recently, a physiological role for macrophages was reported in the regulation and clearing of cerebrovascular amyloid in AD mice (Hawkes and McLaurin, 2009, Weiss, et al, 2010). We showed that activated macrophage cells were present around amyloid depositions in Protollin treated mouse brains and this activation was associated with a reduction in CAA like pathology.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model

Lifshitz

Weiss

Benromano

et al. 2012

Neurobiology of Aging

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Cerebrovascular amyloidosis is caused by amyloid accumulation in walls of blood vessel walls leading to hemorrhagic stroke and cognitive impairment. Transforming growth factor-β1 (TGF-β1) expression levels correlate with the degree of cerebrovascular amyloid deposition in Alzheimer s disease (AD) and TGF-β1 immunoreactivity in such cases is increased along the cerebral blood vessels. Here we show that a nasally administered proteosome-based adjuvant activates macrophages and decreases vascular amyloid in TGF-β1 mice. Animals were nasally treated with a proteosome-based adjuvant on a weekly basis for three months beginning at age 13 months. Using MRI we found that while control animals showed a significant cerebrovascular pathology, proteosome-based adjuvant prevents further brain damage and prevents pathological changes in the blood-brain barrier. Using an object recognition test and Y-maze, we found significant improvement in cognition in the treated group. Our findings support the potential use of a macrophage immuno-modulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage and improve cognition.

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Section: Discussionmentioning

confidence: 99%

Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model

Lifshitz

Weiss

Benromano

et al. 2012

Neurobiology of Aging

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“…Furthermore, increased production of the cytokine TGF-β by astrocytes in a mouse model of AD leads to a significant decrease in parenchymal Aβ accumulation and plaque formation, but also an increased degree of CAA (Wyss-Coray et al, 2001). This effect of TGF-β seems, moreover, to be mediated by increased Aβ phagocytosis by microglia in the brain parenchyma, but decreased phagocytosis by macrophages and microglia in the vicinity of the BBB vasculature (Weiss et al, 2011; Wyss-Coray et al, 1997). This last observation also highlights the importance of myeloid phagocytic cells in AD pathogenesis.…”

Section: Aβ At the Neurovascular Unitmentioning

confidence: 99%

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

Louveau

Mesquita

Kipnis

2016

Neuron

142

119

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Summary Lymphatic vasculature drains interstitial fluids, which contain the tissue’s waste products and ensures immune surveillance of the tissues, allowing immune-cell recirculation. Until recently the central nervous system (CNS) was considered to be devoid of a conventional lymphatic vasculature. The recent discovery in the meninges of a lymphatic network that drains the CNS calls into question classic models for the drainage of macromolecules and immune cells from the CNS. In the context of neurological disorders, the presence of a lymphatic system draining the CNS potentially offers a new player and a new avenue for therapy. In this review, we will attempt to integrate the known primary functions of the tissue lymphatic vasculature that exists in peripheral organs with the proposed function of meningeal lymphatic vessels in neurological disorders, specifically multiple sclerosis and Alzheimer’s disease. We propose that these (and potentially other) neurological afflictions can be viewed as diseases with neuro-lympho-vascular component and should be therapeutically targeted as such.

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“…This hypothesis was built upon several observations. Monocyte/macrophage marker-positive foci/cells colocalized with HCHWA-Dutch arterial Ab (Maat-Schieman et al, 1997); in sporadic CAA, cerebrovascular amyloid deposition, mainly composed of Ab 1-40 peptides, was associated with increased recruitment or activation of monocyte/macrophage lineage cells (Yamada et al, 1996); more recently, data in both mouse models and Ab-related angiitis patients suggested a critical implication of cross-talk between endothelial cells, macrophages and T cells in the modulation of cerebrovascular amyloid deposition and CAA development (Weiss et al, 2011). In vitro, several Ab-peptides induce both CD40 expression, IL-1b and interferon-c secretion from human aortic endothelial cells; this latter finding also suggested that, although pro-inflammatory cytokines may be produced by recruited T cells and macrophages, Ab also functions as a direct inflammatory stimulator of parietal cells (Suo et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

β‐amyloid context intensifies vascular smooth muscle cells induced inflammatory response and de‐differentiation

et al. 2013

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SummarySeveral studies have shown that the accumulation of b-amyloid peptides in the brain parenchyma or vessel wall generates an inflammatory environment. Some even suggest that there is a cause-and-effect relationship between inflammation and the development of Alzheimer's disease and/or cerebral amyloid angiopathy (CAA). Here, we studied the ability of wild-type Ab 1-40 -peptide (the main amyloid peptide that accumulates in the vessel wall in sporadic forms of CAA) to modulate the phenotypic transition of vascular smooth muscle cells (VSMCs) toward an inflammatory/de-differentiated state. We found that Ab 1-40 -peptide alone neither induces an inflammatory response, nor decreases the expression of contractile markers; however, the inflammatory response of VSMCs exposed to Ab 1-40 -peptide prior to the addition of the pro-inflammatory cytokine IL-1b is greatly intensified compared with IL-1b-treated VSMCs previously unexposed to Ab 1-40 -peptide. Similar conclusions could be drawn when tracking the decline of contractile markers. Furthermore, we found that the mechanism of this potentiation highly depends on an Ab 1-40 preactivation of the PI 3 Kinase and possibly NFjB pathway; indeed, blocking the activation of these pathways during Ab 1-40 -peptide treatment completely suppressed the observed potentiation. Finally, strengthening the possible in vivo relevance of our findings, we evidenced that endothelial cells exposed to Ab 1-40 -peptide generate an inflammatory context and have similar effects than the ones described with IL-1b. These results reinforce the idea that intraparietal amyloid deposits triggering adhesion molecules in endothelial cells, contribute to the transition of VSMCs to an inflammatory/de-differentiated phenotype. Therefore, we suggest that acute inflammatory episodes may increase vascular alterations and contribute to the ontogenesis of CAA.

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TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis

Cited by 28 publications

References 49 publications

Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model

Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

β‐amyloid context intensifies vascular smooth muscle cells induced inflammatory response and de‐differentiation

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