Platelets in the Alzheimer’s Disease Brain: do they Play a Role in Cerebral Amyloid Angiopathy?

Kniewallner, Kathrin M.; Ehrlich, Daniela; Kiefer, Andreas; Marksteiner, Josef; Humpel, Christian

doi:10.2174/1567202612666150102124703

Cited by 25 publications

(30 citation statements)

References 60 publications

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“…For decades, platelets have been considered a good model to study the pathophysiology of AD and a promising source of AD biomarkers, because platelets display all the enzymes of an amyloidogenic pathway and generate Aβ peptides ( Figure 1B) [19]. It has been suggested that full-length APP acts as a receptor on the platelet surface and also appears to be crucial in the regulation of intracellular Ca 2+ concentration [20]. The proteolytic cleavage of platelet APP appear to occur both on the platelet cell membrane and within the intracellular compartments, and Aβ can be secreted upon platelet activation [21].…”

Section: Prospective Ad Biomarkers In Plateletsmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Prospective Ad Biomarkers In Plateletsmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…Mouse platelets were isolated as reported previously 12 . Briefly, mice were anaesthetized by an intraperitoneal injection of Ketamine 100 mg/kg and Xylazine 10 mg/kg (AniMedica).…”

Section: Methodsmentioning

confidence: 99%

“…It seems reasonable that an initial deposition of Aβ in early stages of CAA may induce degeneration of the vessel wall leading to dilation of the lumen 11 . However, to date it is not clear if CAA is a primary cause in the development of AD or only a consequence of the Aβ accumulation in the brain 12 .…”

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confidence: 99%

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

Kniewallner

Wenzel

Humpel

2016

Sci Rep

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Strong evidence shows an association between cerebral vascular diseases and Alzheimer´s disease (AD). In order to study the interaction of beta-amyloid (Aβ) plaques with brain vessels, we crossbred an AD mouse model (overexpressing amyloid precursor protein with the Swedish-Dutch-Iowa mutations, APP_SweDI) with mice expressing green fluorescent protein (GFP) under the flt-1/VEGFR1 promoter in vessels (GFP_FLT1). Our data show, that only very few Aβ plaques were seen in 4-months old mice, focused in the mammillary body and in the lateral septal nucleus. The number of plaques markedly increased with age being most prominent in 12-months old mice. Thiazine Red was used to verify the plaques. Several Thiazine Red+ inclusions were found in GFP+ vessels, but only in non-perfused 4-months old mice. These inclusions were verified by Resorufin stainings possibly representing cerebral amyloid angiopathy. The inclusions were also seen in non-crossbred APP_SweDI but not in wildtype and GFP_FLT1 mice. In order to characterize these inclusions Flow Cytometry (FACS) analysis demonstrated that platelets were specifically stained by Thiazine Red+, more pronounced when aggregated. In conclusion, our data show that Thiazine Red+ inclusions representing aggregated platelets are a first pathological sign in AD before plaque development and may become important therapeutic targets in early AD.

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“…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%

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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Platelets in the Alzheimer’s Disease Brain: do they Play a Role in Cerebral Amyloid Angiopathy?

Cited by 25 publications

References 60 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

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

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

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