Exercise-Induced Activated Platelets Increase Adult Hippocampal Precursor Proliferation and Promote Neuronal Differentiation

Leiter, Odette; Seidemann, Suse; Overall, Rupert W.; Ramasz, Beáta; Rund, Nicole; Schallenberg, Sonja; Grinenko, Tatyana; Wielockx, Ben; Kempermann, Gerd; Walker, Tara L.

doi:10.1016/j.stemcr.2019.02.009

Cited by 76 publications

(94 citation statements)

References 56 publications

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“…Additionally, platelets contain up to 95% of the circulating form of the amyloid precursor protein (Zhao et al, 2016), they express several neuronal receptors and inflammatory-signalling molecules (Wojsiat et al, 2017), and also contain α-synuclein (Michell et al, 2005). Recently, it has also been shown that platelets play an active role during adult neurogenesis in the hippocampus (Seidemann et al, 2019). Finally, changes in activation, aggregation and morphology of platelets have been reported in PD, DLB, amyotrophic lateral sclerosis and multiple sclerosis (Behari and Shrivastava, 2013).…”

Section: Introductionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

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_ 3 The paper explained Problem: Dementia with Lewy bodies (DLB) presents pathological and clinical overlap with both Alzheimer's (AD) and Parkinson's disease (PD), which impairs its correct diagnosis. Although numerous papers report peripheral biomarkers for AD, wellestablished biomarkers for DLB distinguishing it from AD are still missing. Platelet miRNA transcriptome was analyzed in several works, but their putative role as disease biomarkers for neurological disorders has not been assessed. It would be of paramount importance to establish a blood-based bio-signature as a minimally invasive mean for DLB diagnosis, improving differentiation of DLB patients from controls and AD. Results:Our study revealed that platelet miRNAs might be promising biomarkers for the correct diagnosis of DLB stratifying patients in comparison with overlapping disorders, especially AD, and may help to highlight possible disease-related processes.In this cross-sectional study, which includes 162 individuals (DLB, AD, PD and healthy controls), platelet-associated miRNA content was disease group-specific. Three different miRNA sets together with their predicted targeted pathways were defined. Impact:This study suggests that platelet miRNA may serve as DLB biomarker allowing the correct diagnosis and stratification in an easily-applied manner in clinical settings, and may help to highlight possible disease-related processes. 4 ABSTRACT Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer's disease (AD) and presents pathological and clinical overlap with both AD and Parkinson's disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a 7-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based bio-signature, which distinguishes DLB from AD.

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Section: Introductionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Changes of peripheral modulators in the blood upon exercise may directly influence NPCs associated with blood vessels and allow crosstalk with each other . Various circulating growth factors are involving in such a crosstalk, such as peripheral vascular endothelial growth factor, platelet factor 4, serotonin and IGF‐1 . Furthermore, recent studies highlighted an essential role of muscle in exercise‐induced cognitive benefits .…”

Section: Discussionmentioning

confidence: 99%

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis

et al. 2019

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Physical exercise-induced enhancement of learning and memory and alleviation of agerelated cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intrahippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exerciseinduced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity.Likewise, lowering Nrf2 expression by RNA interference with bilateral intrahippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration. K E Y W O R D Sadult neurogenesis, exercise, insulin-like growth factor-1, nuclear factor erythroid 2-related factor 2, neural progenitor cell, proteasome

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“…Platelets might not only have detrimental functions in the brain but also beneficial ones. For example, it has recently been demonstrated that the exercise-induced stimulatory effects on adult hippocampal neurogenesis are partially mediated through platelets (Leiter et al, 2019). In the context of stroke and of demyelinating lesions, platelet-derived factors promote neurogenesis and neuroprotection (Hayon et al, 2013;Au et al, 2014;Kazanis et al, 2015).…”

Section: Figure 5 | Continuedmentioning

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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Exercise-Induced Activated Platelets Increase Adult Hippocampal Precursor Proliferation and Promote Neuronal Differentiation

Cited by 76 publications

References 56 publications

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

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