Letter to Editors Iron-induced fibrin formation may explain vascular pathology in Alzheimer’s disease

Lipiński, Bogusław; Pretorius, Etheresia

doi:10.5114/fn.2014.43792

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…APP accumulation in the brain has been extensively evaluated as a sensitive marker for the detection of axonal injury [40-43]. Deposition of fibrin not only contributes to neurodegeneration and neuroinflammation, but may also mimic the vascular pathology of Alzheimer’s disease [9, 44]. Thrombin has an essential role in the blood coagulation cascade, and contributes to BBB dysfunction and neuroinflammation which are early features of Alzheimer's disease [45].…”

Section: Resultsmentioning

confidence: 99%

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

Yu¹,

Venkat²,

Chopp³

et al. 2019

Aging and disease

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Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA -/- ) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA -/- mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA -/- mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA -/- mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.

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Section: Resultsmentioning

confidence: 99%

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

Yu¹,

Venkat²,

Chopp³

et al. 2019

Aging and disease

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“…While we here focus on SARS-CoV-2, we note that all kinds of molecules have been shown to affect the extent of fibrinaloid clot formation, including iron, other amyloids, bacterial cell wall components, etc., and that we have observed them in a variety of chronic, inflammatory diseases including Alzheimer's [37,50,[60][61][62]], Parkinson's disease [37,48], Type 2 diabetes [37,38,62,63,213,214] (where the amyloid protein amylin [215][216][217] is of course a well-known player) and rheumatoid arthritis [65,67].…”

Section: Other Causes Of Amyloid Microclotsmentioning

confidence: 99%

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Kell

Laubscher

Pretorius

2022

Biochemical Journal

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185

212

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Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

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“…Ultrastructurally, in both cases, we observed neurofibrillary pathology and deposits of collagen in the vessel walls of the male proband's brain [10]. Šerý et al [24] suggest that vascular pathology influences pathological pro cesses in Alzheimer's disease [14]. Our report sug gests that FTLD with MAPT mutation affects mainly the CNS, and neuropathological changes depend on the variant of the mutation.…”

Section: Discussionmentioning

confidence: 60%

Frontotemporal lobar degeneration with MAPT mutation in an Italian-Polish family. A

Wierzba-Bobrowicz¹,

Lewandowska²,

Zaremba³

et al. 2014

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Letter to Editors Iron-induced fibrin formation may explain vascular pathology in Alzheimer’s disease

Cited by 5 publications

References 6 publications

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Frontotemporal lobar degeneration with MAPT mutation in an Italian-Polish family. A

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