Can platelet activation result in increased plasma Aβ levels and contribute to the pathogenesis of Alzheimer’s disease?

Carbone, Manuel Glauco; Pagni, G; Tagliarini, Claudia; Imbimbo, Bruno P.; Pomara, Nunzio

doi:10.1016/j.arr.2021.101420

Cited by 19 publications

(15 citation statements)

References 221 publications

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“… 43 In fact, platelets are the primary source (≈90%) of Aβ peptides in human blood. 45 Insulin resistance can cause platelet hyperactivity, 46 which contributes to Aβ overproduction. 43 , 45 …”

Section: Discussionmentioning

confidence: 99%

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Triglyceride–glucose index, Alzheimer's disease plasma biomarkers, and dementia in older adults: The MIND‐China study

Tian

Dong

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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Introduction Population‐based studies have rarely explored the associations of the triglyceride–glucose (TyG) index, a surrogate marker of insulin resistance, with dementia and plasma biomarkers for amyloid beta (Aβ) and neurodegeneration. Methods This population‐based study included 5199 participants (age ≥ 65 years); of these, plasma Aβ, total tau, and neurofilament light chain (NfL) were measured in 1287 persons. Dementia and subtypes were diagnosed following the international criteria. TyG index was calculated as ln(fasting triglyceride(mg/dL) × fasting glucose[mg/dL]/2). Data were analyzed using logistic and general linear regression models. Results Dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were diagnosed in 301, 195, and 95 individuals, respectively. A high TyG index was significantly associated with increased likelihoods of dementia and AD; the significant association with dementia remained among participants without cardiovascular disease or diabetes. In the biomarker subsample, a high TyG index was correlated with elevated plasma Aβ, but not with total tau or NfL. Discussion High TyG index is associated with dementia, possibly via Aβ pathology.

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Section: Discussionmentioning

confidence: 99%

“… 45 Insulin resistance can cause platelet hyperactivity, 46 which contributes to Aβ overproduction. 43 , 45 …”

Section: Discussionmentioning

confidence: 99%

Triglyceride–glucose index, Alzheimer's disease plasma biomarkers, and dementia in older adults: The MIND‐China study

Tian

Dong

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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“…By gene network function and molecular integration analyses, we classified the DEPs into the following 10 clusters: AD, platelet activation, neutrophil degranulation, VEGFA-VEGFR2 signaling pathway, EGF/EGFR signaling pathway, lipid metabolism pathway, fatty acid biosynthesis, glucagon signaling pathway, MAPK signaling pathway, and IL-18 signaling pathway (Figure 5, red represents increased, blue represents decreased, and the inner and outer circles represent platelets and TC brain regions), all of which were closely related to neurological diseases including AD. [21][22][23][24][25][26] We also observed that the AD-related molecules, including ADAM10, PPP3CB, RTN4, BAX, ITPR1, ITPR2, NDUFA13, FADD, RELA, TRAF2 and MAP4K2, SOS1, and ERBIN, were the most significantly enriched nodes (Figure 5). ADAM10 showed the highest connectivity in the whole pathway and a decreased consistency in the Together, the comprehensive integrative analysis of platelet and brain omics data demonstrated that the molecular changes in platelet can well reflect the pathological mechanism of the brain in AD patients, which provides high-confidence platelet targets for future large-scale validation in AD-related population (Figure 5), highlighting the key regulator role of HMOX2 and SERPINA3 in AD, as well as the potential diagnostic value of RTN1 and IDH3B.…”

Section: Integrated Bioinformatics and Machine Learning Establishes H...mentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Integrated analyses of brain and platelet omics reveal their common altered and driven molecules in Alzheimer's disease

Pan

et al. 2022

MedComm

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Platelets may serve as a perfect peripheral source for exploring diagnostic biomarkers for Alzheimer's disease (AD); however, the molecular linkage between platelet and the brain is missing. To find the common altered and driving molecules in both brain and the platelet, we performed an integrated analysis of our platelet omics and brain omics reported in the literature, and analyzed their correlations with AD‐specific pathology and cognitive impairment. By integrating the gene and protein expression profiles from 269 AD patients, we deduced 239 differentially expressed proteins (DEPs) appeared in both brain and the platelet, and 70.3% of them had consistent changes. Further analysis demonstrated that the altered brain and peripheral regulations were pinpointed into 10 imbalanced pathways. We also found that 117 DEPs, including ADAM10, were closely associated to the AD‐specific β‐amyloid and tau pathologies; and the changes of IDH3B and RTN1 had a potential diagnostic value for cognitive impairment analyzed by machine learning. Finally, we identified that HMOX2 and SERPINA3 could serve as driving molecules in neurodegeneration, and they were increased and decreased in AD patients, respectively. Together, this integrated brain and platelet omics provides a valuable resource for establishing efficient peripheral diagnostic biomarkers and potential therapeutic targets for AD.

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“…As one hallmark of cerebral I/R injury, BBB breakdown in the ischemic period is exacerbated by reperfusion and followed by a no-reflow phenomenon of capillaries ( Mohamed Mokhtarudin and Payne, 2015 ; Burrows et al, 2016 ; Huang et al, 2020 ). In addition to intracerebral Aβ retention caused by microcirculation disturbance, activated platelets contained in microthrombosis during the ischemic period and after I/R are demonstrated as the potential peripheral source of acute Aβ accumulation in blood vessels including capillaries and nearby brain tissues ( Martins et al, 2019 ; Carbone et al, 2021 ). Aβ accumulation in the brain can raise the formation of a toxic Aβ-like Aβ 1-42 oligomer, cause swelling in astrocytic endfeet, and also lead to dysregulation of capillaries by acting on pericytes, impairing energy supply for neurons ( Merlini et al, 2011 ; Cavallucci et al, 2012 ; Nortley et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood–Brain Barrier–Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats

Lyu

et al. 2021

Front. Pharmacol.

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Background: The dysfunctional blood–brain barrier (BBB)–glymphatic system is responsible for triggering intracerebral amyloid-beta peptide (Aβ) accumulation and acts as the key link between ischemic stroke and dementia dominated by Alzheimer’s disease (AD). Recently, pyroptosis in cerebral ischemia and reperfusion (I/R) injury is demonstrated as a considerable mechanism causing BBB–glymphatic dysfunctions and Aβ acute accumulation in the brain. Targeting glial pyroptosis to protect BBB–glymphatic functions after cerebral I/R could offer a new viewpoint to prevent Aβ accumulation and poststroke dementia. Yi-Zhi-Fang-Dai formula (YZFDF) is an herbal prescription used to cure dementia with multiple effects of regulating inflammatory responses and protecting the BBB against toxic Aβ-induced damage. Hence, YZFDF potentially possesses neuroprotective effects against cerebral I/R injury and the early pathology of poststroke dementia, which evokes our current study.Objectives: The present study was designed to confirm the potential efficacy of YZFDF against cerebral I/R injury and explore the possible mechanism associated with alleviating Aβ acute accumulation.Methods: The models of cerebral I/R injury in rats were built by the method of middle cerebral artery occlusion/reperfusion (MCAO/R). First, neurological function assessment and cerebral infarct measurement were used for confirming the efficacy of YZFDF on cerebral I/R injury, and the optimal dosage (YZFDF-H) was selected to conduct the experiments, which included Western blotting detections of pyroptosis, Aβ1-42 oligomers, and NeuN, immunofluorescence observations of glial pyroptosis, aquaporin-4 (AQP-4), and Aβ locations, brain water content measurement, SMI 71 (a specific marker for BBB)/AQP-4 immunohistochemistry, and Nissl staining to further evaluate BBB–glymphatic functions and neuronal damage.Results: YZFDF obviously alleviated neurological deficits and cerebral infarct after cerebral I/R in rats. Furthermore, YZFDF could inactivate pyroptosis signaling via inhibiting caspase-1/11 activation and gasdermin D cleavage, ameliorate glial pyroptosis and neuroinflammation, protect against BBB collapse and AQP-4 depolarization, prevent Aβ acute accumulation and Aβ1-42 oligomers formation, and reduce neuronal damage and increase neurons survival after reperfusion.Conclusion: Our study indicated that YZFDF could exert neuroprotective effects on cerebral I/R injury and prevent Aβ acute accumulation in the brain after cerebral I/R associated with inhibiting neuroinflammation-related pyroptosis and BBB–glymphatic dysfunctions.

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Can platelet activation result in increased plasma Aβ levels and contribute to the pathogenesis of Alzheimer’s disease?

Cited by 19 publications

References 221 publications

Triglyceride–glucose index, Alzheimer's disease plasma biomarkers, and dementia in older adults: The MIND‐China study

Triglyceride–glucose index, Alzheimer's disease plasma biomarkers, and dementia in older adults: The MIND‐China study

Integrated analyses of brain and platelet omics reveal their common altered and driven molecules in Alzheimer's disease

Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood–Brain Barrier–Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats

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