Introduction: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants.
Methods: Adults (45-65 years) with a parental history of AD were enrolled (n = 82).
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View Article and Find Full Text PDFMid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies.
View Article and Find Full Text PDFObservations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer's disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.
View Article and Find Full Text PDFVascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling.
View Article and Find Full Text PDFDefects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains.
View Article and Find Full Text PDFWe have examined the roles of the endothelin-converting enzyme-1 and -2 (ECE-1 and ECE-2) in the homeostasis of α-synuclein (α-syn) and pathogenesis of Lewy body disease. The ECEs are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin-1 (EDN1). We have found that ECE-1 and ECE-2 cleave and degrade α-syn in vitro and siRNA-mediated knockdown of ECE-1 and ECE-2 in SH-SY5Y neuroblastoma cells significantly increased α-syn both intracellularly (within the cell lysate) (p < 0.
View Article and Find Full Text PDFEpidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD.
View Article and Find Full Text PDFAims: Deposition of amyloid beta (Aβ) in the brain is one of the defining abnormalities of Alzheimer's disease (AD). Phosphorylation of Aβ at serine 8 (pAβ) has been implicated in its aggregation in vitro and pAβ level has been shown to be significantly elevated in AD. We aimed to assess the specificity of pAβ for AD and have investigated associations of pAβ with parenchymal and cerebrovascular accumulation of Aβ, disease progression, angiotensin-converting enzyme activity and APOE genotype.
View Article and Find Full Text PDFAmyloid-β peptide (Aβ), the cerebral accumulation of which is thought to cause Alzheimer's disease (AD), is produced throughout life. The level of insoluble Aβ rises with age and is further increased in AD. In contrast, we showed previously that in mid-frontal cortex in a cohort without neurological disease, soluble Aβ declined progressively between 16 and 95 y.
View Article and Find Full Text PDFJ Neuropathol Exp Neurol
November 2011
There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce Aβ levels and protect against cognitive impairment in mouse models of AD. The activity of several Aβ-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of Aβ.
View Article and Find Full Text PDFNeprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA.
View Article and Find Full Text PDFWe previously reported age- and Alzheimer's disease (AD)-related increases in the activities of β-secretase (BACE-1) and Aβ-degrading enzymes including neprilysin (NEP) and angiotensin-converting enzyme (ACE) in the frontal cortex. We suggested that these increases were secondary to the accumulation of insoluble amyloid-β (Aβ) and a decline in soluble Aβ. We have further tested this hypothesis by examination of frontal cortex obtained postmortem from individuals with Down's syndrome (DS), in whom AD-like neuropathological changes occur in association with early-onset dementia.
View Article and Find Full Text PDFDespite accumulating evidence of a central role for oligomeric amyloid beta (Abeta) in the pathogenesis of Alzheimer's Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric Abeta and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric Abeta to be associated with both diffuse and neuritic plaques (mostly co-localized with Abeta(1-42)) and with cerebrovascular deposits of Abeta in paraffin sections of formalin-fixed human brain tissue. The amount of oligomeric Abeta that was labeled in the sections correlated with total Abeta plaque load, but not phospho-tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype.
View Article and Find Full Text PDFExperimental reduction of neprilysin (NEP) or insulin-degrading enzyme (IDE) in vivo exacerbates beta-amyloid accumulation in the brain. The level of these enzymes is reportedly reduced during aging and in postmortem brains of patients with sporadic Alzheimer disease (AD). To distinguish between primary decreases in NEP and IDE activity that might contribute to beta-amyloid accumulation and decreases secondary to neurodegenerative changes in AD, we measured NEP and IDE levels by indirect sandwich ELISA and enzyme activities by immunocapture-based fluorogenic assays in postmortem frontal cortex from patients of different ages and at different pathological stages of AD, as indicated by Braak tangle stage.
View Article and Find Full Text PDFIn Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta.
View Article and Find Full Text PDFInternally quenched fluorogenic substrates are commonly used for measuring enzyme activity in biological samples and allow high sensitivity and continuous real-time measurement that is well suited for high throughput analysis. We describe the development and optimisation of an immunocapture-based assay that uses the fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)) and allows the specific measurement of insulin-degrading enzyme (IDE) activity in brain tissue homogenates. This fluorogenic substrate can be cleaved by a number of enzymes including neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1) and angiotensin-converting enzyme (ACE), as well as IDE, and we have previously shown that discrimination between these individual enzymes is not readily achieved in tissue homogenates, even in the presence of selective inhibitors and pH conditions.
View Article and Find Full Text PDFNeprilysin, a zinc-metalloendopeptidase, has important roles in the physiology and pathology of many diseases such as hypertension, cancer and Alzheimer's disease. We have developed an immunocapture assay to measure the specific enzyme activity of neprilysin in brain tissue homogenates and cerebrospinal fluid (CSF). The assay uses a neprilysin-specific antibody, previously used in a commercially available ELISA kit, to isolate and immobilise NEP from brain homogenates and CSF, prior to the addition of a fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)).
View Article and Find Full Text PDFNeprilysin (NEP) degrades amyloid-beta (Abeta) and is thought to contribute to its clearance from the brain. In Alzheimer disease (AD), downregulation of NEP has been suggested to contribute to the development of cerebral amyloid angiopathy (CAA). We examined the relationship among NEP, CAA, and APOE status in AD and elderly control cases.
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