Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

Roher, Alex E.; Esh, Chera L.; Kokjohn, Tyler A.; Castaño, Eduardo M.; Vickle, Gregory D. Van; Kalback, Walter M.; Patton, R. Lyle; Luehrs, Dean C.; Daugs, Ian D.; Kuo, Yu Min; Emmerling, Mark R.; Soares, Holly; Quinn, Joseph F.; Kaye, Jeffrey; Connor, Donald J.; Silverberg, Nina; Adler, Charles H.; Seward, James D.; Beach, Thomas G.; Sabbagh, Marwan N.

doi:10.1016/j.jalz.2008.10.004

Cited by 344 publications

(304 citation statements)

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“…Future studies will help to elucidate the crosstalk between innate immunity and adaptive 169,170 . § Aβ might also be generated by skin fibroblasts and osteoblasts 5,[171][172][173] , although these findings have not yet been confirmed. Aβ, amyloid-β.…”

Section: Disorders Of Systemic Immunitymentioning

confidence: 93%

“…Plasma Aβ levels inversely correlate with liver function, suggesting that hepatic dysfunction attenuates peripheral Aβ clearance 108 . Liver tissue from patients with AD contains less Aβ than that from healthy individuals, which implies that the Aβ-clearance function of liver is compromised in patients with AD 5 .…”

Section: Hepatic Dysfunctionmentioning

confidence: 99%

“…adrenal gland, kidney, heart, liver, spleen, pancreas, muscles, and various blood and endothelial cells 4,5 . Aβ levels (in both peripheral tissues and the brain) are known to be lower in cognitively normal elderly individuals than in patients with AD (TABLE 1).…”

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confidence: 99%

“…APP 695 is the dominant species produced by neurons, whereas APP 751 and APP 770 are the dominant species produced by peripheral cells, including platelets and leukocytes 6 . Another possible explanation is that the tissue microenvironment differs between the CNS and periphery, which could result in differential processing of APP by γ-secretase and generation of different Aβ species 4,5 . Second, levels of Aβ in the central pool are higher than those in the peripheral pool.…”

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confidence: 99%

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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Disorders Of Systemic Immunitymentioning

confidence: 93%

Section: Hepatic Dysfunctionmentioning

confidence: 99%

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confidence: 99%

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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…We showed that a 1:3 A␤:fibrinogen ratio produced delayed lysis ( Figure 1B). Although plasma A␤ concentrations are low, 32 local concentrations can be high due to release of A␤ by platelets at the site of thrombus Plasminogen binding to fibrin monolayers exposed to 2M A␤42 or vehicle was measured by ELISA and normalized to samples not containing plasminogen. Plasminogen binding was decreased in the presence of A␤ (P ϭ .04).…”

Section: Discussionmentioning

confidence: 99%

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

Zamolodchikov

Strickland

2012

Blood

157

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Alzheimer disease is characterized by the presence of increased levels of the ␤-amyloid peptide (A␤) in the brain parenchyma and cerebral blood vessels. This accumulated A␤ can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that A␤ 42 specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, A␤ 42 -induced structural changes cannot be the sole mechanism of delayed lysis because A␤ overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that A␤ interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing A␤ 42 , and clot lysis by plasmin, but not trypsin, is IntroductionCerebrovascular dysfunction has been implicated as an early event in Alzheimer disease (AD) progression, 1-4 but the origins and mechanisms of vascular dysfunction in AD are not clear. The ␤-amyloid peptide (A␤) accumulates in the brain parenchyma and blood vessel walls of AD patients and has been genetically and clinically linked to AD. We have previously shown that fibrinogen, the main protein component of blood clots, can bind A␤ 42 (henceforth designated A␤) specifically with a K d of 26.3 Ϯ 6.7nM. 5 We also found that fibrin clots formed in the presence of A␤ are structurally altered and more resistant to fibrinolysis than normal clots. 6 However, the mechanism by which A␤-fibrin(ogen) binding delays fibrin clot lysis has not been defined.Fibrin clot lysis is mediated by plasmin, a serine protease that cleaves the fibrin network at specific sites. Plasmin is derived from plasminogen by tissue plasminogen activator (tPA) in the presence of fibrin, which itself enhances the rate of the reaction. One fibrin site initially involved in plasminogen activation by tPA includes residues 148-160 on the A␣-chain (reviewed by Medved and Nieuwewnhuizen 7 ). This site becomes exposed and available for plasminogen binding after the conversion of fibrinogen to fibrin, 8 but could remain hidden if clots are formed in the presence of A␤, leading to delayed clot lysis. This hypothesis is derived from our finding that A␤ binds the fibrinogen ␤-chain near the ␤-hole, 5 which is in close spatial proximity to residues 148-160 of the A␣-chain. 9 Another potential explanation for delayed clot lysis is based on the relationship between fibrin structure and its susceptibility to fibrinolysis. Tighter fibrin networks composed of thin fibers are degraded less efficiently by plasmin than those composed of thick fibers 10-13 because: (1) there are more fibers to be cleaved, 11,14 requiring plasmin to detach from and move between fibers more frequently 15 ; and (2) decreased network porosity of tighter fibrin networks results in impeded diffusion of fibrinolytic enzymes throughout the clot (...

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Neurotrauma Biomarker Levels and Adverse Symptoms Among Military and Law Enforcement Personnel Exposed to Occupational Overpressure Without Diagnosed Traumatic Brain Injury

et al. 2021

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Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

Abstract: Background-We evaluated the amounts of amyloid-beta (Aβ) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.

Cited by 344 publications

References 73 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

Neurotrauma Biomarker Levels and Adverse Symptoms Among Military and Law Enforcement Personnel Exposed to Occupational Overpressure Without Diagnosed Traumatic Brain Injury

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