Alzheimer's disease and angiogenesis

Vagnucci, Anthony H; Li, William W.

doi:10.1016/s0140-6736(03)12521-4

Cited by 240 publications

(168 citation statements)

References 27 publications

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“…7B Previous reports have shown that inflammation is critically involved in the pathogenesis of Alzheimer's disease (39). Moreover, A␤42 peptide is one of the enzymatic cleavage fragments of amyloid precursor protein (40) and has been reported to play a significant role in the proinflammatory responses of systemic amyloidosis, such as Alzheimer's disease (39,40). Recently, A␤42 peptide was found to bind to FPRL1 and to modulate the generation of reactive oxygen species and cellular chemotactic migration in human neutrophils via FPRL1 (30).…”

Section: Wrw 4 Inhibits A␤42 Peptide-induced Superoxide Generation Anmentioning

confidence: 99%

Identification of Peptides That Antagonize Formyl Peptide Receptor-Like 1-Mediated Signaling

Bae

Lee

et al. 2004

The Journal of Immunology

150

119

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Formyl peptide receptor-like 1 (FPRL1) is an important classical chemoattractant receptor that is expressed in phagocytic cells in the peripheral blood and brain. Recently, various novel agonists have been identified from several origins, such as host-derived molecules. Activation of FPRL1 is closely related to inflammatory responses in the host defense mechanism and neurodegenerative disorders. In the present study we identified several novel peptides by screening hexapeptide libraries that inhibit the binding of one of FPRL1’s agonists (Trp-Lys-Tyr-Met-Val-d-Met-CONH2 (WKYMVm)) to its specific receptor, FPRL1, in RBL-2H3 cells. Among the novel peptides, Trp-Arg-Trp-Trp-Trp-Trp-CONH2 (WRWWWW (WRW4)) showed the most potent activity in terms of inhibiting WKYMVm binding to FPRL1. We also found that WRW4 inhibited the activation of FPRL1 by WKYMVm, resulting in the complete inhibition of the intracellular calcium increase, extracellular signal-regulated kinase activation, and chemotactic migration of cells toward WKYMVm. For the receptor specificity of WRW4 to the FPR family, we observed that WRW4 specifically inhibit the increase in intracellular calcium by the FPRL1 agonists MMK-1, amyloid β42 (Aβ42) peptide, and F peptide, but not by the FPR agonist, fMLF. To investigate the effect of WRW4 on endogenous FPRL1 ligand-induced cellular responses, we examined its effect on Aβ42 peptide in human neutrophils. Aβ42 peptide-induced superoxide generation and chemotactic migration of neutrophils were inhibited by WRW4, which also completely inhibited the internalization of Aβ42 peptide in human macrophages. WRW4 is the first specific FPRL1 antagonist and is expected to be useful in the study of FPRL1 signaling and in the development of drugs against FPRL1-related diseases.

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Section: Wrw 4 Inhibits A␤42 Peptide-induced Superoxide Generation Anmentioning

confidence: 99%

Identification of Peptides That Antagonize Formyl Peptide Receptor-Like 1-Mediated Signaling

Bae

Lee

et al. 2004

The Journal of Immunology

150

119

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“…Leakiness of the BBB has been demonstrated in a number of AD transgenic animal models that have overexpression of APP, including the Tg2576, which manifests a form of early-onset AD [24,25]. Studies show that BBB integrity is compromised in this mouse model as early as 4 months of age, much before the onset of other disease pathology, such as the consolidated amyloid plaques [24,27]. Hence, the mechanism leading to the BBB disruption is a potential target for AD therapy.…”

Section: Alzheimer's Disease and The Blood-brain Barrier Pathogenesismentioning

confidence: 94%

“…Albumin is a macromolecule that is unable to cross an intact BBB [27,28]. Histological studies have also revealed the presence of albumin staining around microvessels that shows co-localization of amyloid plaques and angiopathy [12,13,26].…”

Section: Tight Junction Disruption In Mouse Modelsmentioning

confidence: 99%

“…Paradoxical to this hypothesis, aggregated Aβ can be extensively present in the human brain in the absence of AD symptoms [56][57][58]. Although Aβ plays a crucial role in AD, it is neither necessary nor by itself sufficient to cause full AD pathology [27]. The alternate idea is that the mere production of Aβ (amyloidogenesis), promotes extensive pathological angiogenesis, leading to the redistribution of TJs, which then causes disruption to the BBB integrity, thereby increasing vascular permeability, subsequent hypervascularization and eventual AD pathology.…”

Section: Angiogenesis: Inflammation and Vascular Activationmentioning

confidence: 99%

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Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

Singh¹,

Pfeifer²,

Jefferies³

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Vascular dysfunction is a crucial pathological hallmark of Alzheimer's disease (AD). Studies have reported that beta amyloid (Aβ) causes increased blood vessel growth in the brains of AD mouse models, a phenomenon that is also seen in AD patients. This has given way to an alternative angiogenesis hypothesis according to which, increased leakiness in the blood vessels disrupts the blood-brain barrier (BBB) and allows unwanted blood products to enter the brain causing progression of disease pathology, promoting amyloid clumping and aggregation along with impaired cerebral blood flow. Furthermore, the expression of melanotransferrin in AD model and patients may contribute to angiogenesis. The objective of this chapter is to attempt to establish a link between the vascular damage and AD pathology. Curbing the vascular changes and resulting damage seen in the brains of AD model mice and improving their cognition by treating with FDA-approved anti-angiogenic drugs may expedite the translational potential of this research into clinical trials in human patients. This direction into targeting angiogenesis will facilitate new preventive and therapeutic interventions for AD and related vascular diseases.

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“…Altered cellular metabolism and oxidative stress within AD-related cerebral hypoperfusion, in the presence of vascular risk factors, might favor the reach of a critical threshold for cerebral hypoperfusion (de la Torre 2000(de la Torre , 2013. The resulting increase in oxidative stress might damage the neurovascular unit and the endothelium of brain vessels thereby favoring Ab formation and nourishing a vicious circle in which plaque-induced ROS formation also damages the neurovascular unit through the endothelium (Vagnucci and Li 2003). ROS and other free radical species production is an early event in AD development, and the disturbed balance between oxidant and antioxidant production has been shown to be associated with the severity of cognitive impairment even in the absence of dementia or with the degree of cognitive performance in healthy subjects across a wide of age range.…”

Section: Why Do We Need To Care About Dementiamentioning

confidence: 99%

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

Polidori

Schulz

2014

Genes Nutr

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There is an impressing body of evidence supporting the beneficial role of balanced nutrition in lowering the risk of dementia and its commonest form, Alzheimer's disease. Nevertheless, and despite worldwide dementia epidemic, there is much unfounded skepticism and lack of information among physicians. As a result, the diagnosis of cognitive impairment occurs still far too late, at best symptomatic drugs keep being prescribed and patients and caregivers are left with little concrete support in the hands of the natural history of the disease. This review summarizes knowledge about the impact of nutrition as part of a healthy lifestyle and of micronutrients in particular on delaying and avoiding dementia onset.Why do we need to care about dementia Dementia is the most prevalent neurodegenerative disorder, and it is characterized by progression, multiple etiology, complex symptomatology including that related to a disturbance of cognitive performance and absence of a cure. During the course of the disease, the cognitive symptoms of dementia persist and steadily worsen and behavioral disturbances appear and progress and as a result intellectual and social abilities are affected enough to obstacle the performance of activities of daily living. According to dementia definition, a diagnosis of dementia can be done when the impairment of more cognitive domains lasts long enough and is associated with behavioral disturbances both affecting activities of daily living. Dementia is indeed associated with disability and a high grade of dependence on caregivers-usually family members. This condition of disability and dependence brings along an enormous social and economic burden which is linked to the epidemics of dementia and its commonest, untreatable form, Alzheimer's disease (AD). The major risk factor for dementia and AD is advanced age, and therefore, the societal impact of AD is increasing according to aging demographics (http:// ec.europa.eu/health/reports/european). Life expectancy at birth in the EU increased from 72 years in 1980 to 78 years in 2007. The population of industrialized countries progressed from a mean life expectancy of 35 years at the beginning of the last century, to currently over 80 years of age. People aged 65 years or older are expected to double between 1995 and 2050 to reach 135 million in the EU, with very old people, aged 80 years and older, being projected to grow as much as eight to ten times on the global scale by 2050. This will strongly impact the already challenging number of ten million AD cases in the EU. As a cure against dementia has not been found yet, health care professionals all over the world are predicted to face the diagnostic, therapeutic and socioeconomical challenges of over 115 million people with dementia by 2050 (Prince et al. 2013). This perspective might be even underestimated, particularly due to inadequate diagnosis, lack of awareness and low education. The dramatic loss of synapses and cholinergic neurons, accumulation of extracellular b amyloid (Ab) plaqu...

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Alzheimer's disease and angiogenesis

Cited by 240 publications

References 27 publications

Identification of Peptides That Antagonize Formyl Peptide Receptor-Like 1-Mediated Signaling

Identification of Peptides That Antagonize Formyl Peptide Receptor-Like 1-Mediated Signaling

Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

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