Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Kniewallner, Kathrin M.; Wenzel, Daniela; Humpel, Christian

doi:10.1038/srep28447

Cited by 20 publications

(26 citation statements)

References 35 publications

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“…15, 61 Beyond their role in hemostasis, platelets and platelet-derived microparticles may contribute to the progression of atherosclerosis. 63 Platelet aggregation may be an early event in the pathogenesis of Alzheimer’s disease, 64, 65 as platelets promote aggregation of β-amyloid through integrin and chaperone-dependent mechanisms. 65 …”

Section: Part I Cerebrovascular Disease: the Prelude To Strokementioning

confidence: 99%

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Silva

Chen

et al. 2017

Circulation Research

333

237

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The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury following ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier (BBB) is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in BBB integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

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Section: Part I Cerebrovascular Disease: the Prelude To Strokementioning

confidence: 99%

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Silva

Chen

et al. 2017

Circulation Research

333

237

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“…In this context, blood components of emerging interest are platelets. For example, platelets are actively involved in the onset and development of cerebral amyloid angiopathy (CAA), a vascular pathology common among AD patients, which is characterized by platelet-derived Aβ depositions (Gowert et al, 2014;Jarre et al, 2014;Kniewallner et al, 2016Kniewallner et al, , 2018. Interestingly, injections of platelets isolated from APP-Swedish Dutch Iowa mice, which is an AD transgenic mouse model with CAA pathology, into healthy age-matched control mice caused vessel damage, whereas WT platelet injection failed to do so (Kniewallner et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In the context of CAA, platelets have been shown to accumulate at cerebrovascular Aβ deposits, where they seem to fuel Aβ deposition (Gowert et al, 2014;Kniewallner et al, 2015Kniewallner et al, , 2016. To assess whether intra-parenchymal platelets might promote similar effects, we analyzed the localization of CD41 + platelets within the brain with respect to Thioflavin S + amyloid plaques.…”

Section: Platelets In the Brain Parenchyma Tightly Associate With Astmentioning

confidence: 99%

“…In the context of brain aging and neurodegeneration, bloodderived elements with therapeutic potential are platelets. Platelets have repeatedly been hypothesized to play a role in AD pathology (Li et al, 1998;Evin et al, 2003), in particular, in cerebral amyloid angiopathy (CAA) (Gowert et al, 2014;Jarre et al, 2014;Donner et al, 2016;Kniewallner et al, 2016Kniewallner et al, , 2018. Platelets are small anuclear blood cells, which store a plethora of bioactive factors in specialized cytoplasmic compartments (Rumbaut and Thiagarajan, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the APP-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In APP-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, APP-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

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“…Interestingly, prior to Aß plaque formation, aggregated platelets were shown as a first pathological sign in AD mouse model, suggesting platelets as therapeutic target in early AD ( 182 ). Indeed, Donner et al.…”

Section: Contribution Of Platelets To Neurovascular Inflammation In Nmentioning

confidence: 99%

Platelets as Mediators of Neuroinflammation and Thrombosis

et al. 2020

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Beyond platelets function in hemostasis, there is emerging evidence to suggest that platelets contribute crucially to inflammation and immune responses. Therefore, considering the detrimental role of inflammatory conditions in severe neurological disorders such as multiple sclerosis or stroke, this review outlines platelets involvement in neuroinflammation. For this, distinct mechanisms of platelet-mediated thrombosis and inflammation are portrayed, focusing on the interaction of platelet receptors with other immune cells as well as brain endothelial cells. Furthermore, we draw attention to the intimate interplay between platelets and the complement system as well as between platelets and plasmatic coagulation factors in the course of neuroinflammation. Following the thorough exposition of preclinical approaches which aim at ameliorating disease severity after inducing experimental autoimmune encephalomyelitis (a counterpart of multiple sclerosis in mice) or brain ischemia-reperfusion injury, the clinical relevance of platelet-mediated neuroinflammation is addressed. Thus, current as well as future propitious translational and clinical strategies for the treatment of neuro-inflammatory diseases by affecting platelet function are illustrated, emphasizing that targeting platelet-mediated neuroinflammation could become an efficient adjunct therapy to mitigate disease severity of multiple sclerosis or stroke associated brain injury.

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Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Cited by 20 publications

References 35 publications

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

Platelets as Mediators of Neuroinflammation and Thrombosis

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