VEGF genetic variability is associated with increased risk of developing Alzheimer's disease

Bo, Roberto Del; Ghezzi, Serena; Scarpini, Elio; Bresolin, Nereo; Comi, Giacomo P.

doi:10.1016/j.jns.2009.02.318

Cited by 35 publications

(18 citation statements)

References 27 publications

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“…The latter correlation is of particular relevance, given the increasing evidence linking the VEGF pathway to AD pathology, and angiogenesis being hypothesized to play an active part in AD pathology [29]. A VEGF gene polymorphism has been associated with increased risk of AD [47, 48], and Aβ was reported to block VEGFR-2-mediated signalling [49]. In mouse models of AD, VEGF was shown to increase neurogenesis and restore memory impairment [50–52].…”

Section: Discussionmentioning

confidence: 99%

Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients

Bridel¹,

Hoffmann

Meyer

et al. 2017

Alz Res Therapy

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BackgroundPyroglutamylation of truncated Aβ peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Aβ species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-Aβ species have been identified as major constituents of Aβ plaques and reduction of pE-Aβ species is associated with improvement of cognitive tasks in animal models of Alzheimer’s disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or Aβ peptides may serve as pharmacodynamic read-outs for QC inhibition.MethodsQC activity, Aβ peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (Aβ42, tau and p-tau) and clinical features was evaluated.ResultsQC activity shows a tendency to decrease with AD progression (p = 0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUCTAU = 0.878, ROC-AUCTAU&QC = 0.939 and ROC-AUCpTAU = 0.820, ROC-AUCpTAU&QC = 0.948). In AD and controls, QC activity correlates with Aβ38 (r = 0.83, p < 0.0001) and Aβ40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r > 0.5, p < 0.0001) and core diagnostic biomarkers (r > 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype.ConclusionsAβ38, Aβ40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0266-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients

Bridel¹,

Hoffmann

Meyer

et al. 2017

Alz Res Therapy

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“…Many of these effects relate to health factors that may modulate AD risk (Launer et al, 2000; Del Bo et al, 2009; Solomon et al, 2009; Lee et al, 2010; Matsuzaki et al, 2011; Piriz et al, 2011; Vargas et al, 2011; Crane et al, 2013; Tolppanen et al, 2013; Di Meco et al, 2014). Additionally, physical activity (Benedict et al, 2013), obesity (Debette et al, 2010; Raji et al, 2010; Cole et al, 2013), and blood glucose (Mortby et al, 2013) have all been associated with brain volume in cognitively intact adults.…”

Section: Discussionmentioning

confidence: 99%

Physical activity, inflammation, and volume of the aging brain

et al. 2014

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Physical activity influences inflammation, and both affect brain structure and Alzheimer’s disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3 ± 4.8 years) and 39 patients with AD (81.9 ± 5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

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“…For example, upregulation of SEMA3A has been linked to schizophrenia and Alzheimer disease, 53 , 54 downregulation of Sema5a has been observed in autism 55 and Sema3f binding by the fragile X mental retardation protein (FMRP) has been implicated in fragile X mental retardation pathology 56 . Furthermore, genetic variation of VEGFA has been associated with motor neuron disease 57 and Alzheimer disease 58 . Whether the link of semaphorins and VEGFs to these disorders involves synaptic effects remains to be investigated.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity

Tillo

Ruhrberg

Mackenzie

2012

Cell Adhesion & Migration

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Synapse formation, maintenance and plasticity are critical for the correct function of the nervous system and its target organs. During development, these processes enable the establishment of appropriate neural circuits. During adulthood, they allow adaptation to both physiological and environmental changes. In this review, we discuss emerging roles for two families of classical axon and vascular guidance cues in synaptogenesis and synaptic plasticity, the semaphorins and the vascular endothelial growth factors (VEGFs). Their contribution to synapse formation and function add a new facet to the spectrum of overlapping and complementary roles for these molecules in development, adulthood and disease.

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VEGF genetic variability is associated with increased risk of developing Alzheimer's disease

Cited by 35 publications

References 27 publications

Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients

Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer’s disease patients

Physical activity, inflammation, and volume of the aging brain

Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity

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