Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer

Spies, Petra E.; Verbeek, Marcel M.; Groen, Thomas van; Claassen, J.A.H.R.

doi:10.2741/4035

Cited by 44 publications

(37 citation statements)

References 81 publications

(64 reference statements)

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“…Given its clear pharmacological implications (Panza et al ., ; Imbimbo & Giardina, ), we have further explored the distribution and activity of γ‐secretase related to amyloid pathology in a larger sample pool of AD and control cases, using [ 3 H]‐L‐685,458 as the radiotracer. While CSF Aβ levels are generally considered to be derived from the brain (Spies et al ., ), it is of biological and clinical relevance to determine whether additional cellular contributors exist, in particular, the choroid plexus (CP; Yan et al ., ; Patel et al ., ). We therefore explored this possibility in the present study in vivo and in vitro .…”

Section: Introductionmentioning

confidence: 99%

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Liu

Xue

Deng

et al. 2013

Eur J of Neuroscience

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Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD.

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Section: Introductionmentioning

confidence: 99%

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Liu

Xue

Deng

et al. 2013

Eur J of Neuroscience

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“…The Aβ42 to Aβ40 ratio was calculated to normalize the Aβ42 production concentrations to the total amount of Aβ (Aβ40 is the most abundant Aβ species in CSF). 25–27 The ratio of total tau (or P-tau 181 ) to Aβ42 was also evaluated because it has been shown to be a predictor of future cognitive decline in elderly cohorts. 17,28–30 It must be stated at the outset that the focus of this study is on the clinical utility of the biomarker and that conclusions drawn from one assay can be confirmed or qualified with data derived from another immunoassay.…”

Section: Methodsmentioning

confidence: 99%

Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age

et al. 2015

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IMPORTANCE Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. OBJECTIVE To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. DESIGN, SETTING, AND PARTICIPANTS As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 ( Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau 181 ), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. MAIN OUTCOMES AND MEASURESChanges in Aβ40, Aβ42, total tau, P-tau 181 , VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.RESULTS While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P Յ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau 181 , and VILIP-1) dramatically increased in some individuals in mid and late middle age (P Յ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P Յ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. CONCLUSIONS AND RELEVANCELongitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeti...

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“…In addition, a decrease in the number of megalin in the choroid plexus disrupted its function with respect to transporting Aβ from the brain to the CSF . If Aβ clearance is reduced, an increase in Aβ aggregation in the brain occurs . It is possible that LCN2 and Aβ could share their transporters in the AD pathology condition via the same receptors.…”

Section: The Expression Of Lcn2 and Its Receptors In The Brain In Casmentioning

confidence: 99%

“…58,59 If Aβ clearance is reduced, an increase in Aβ aggregation in the brain occurs. 60,61 It is possible that LCN2 and Aβ could share their transporters in the AD pathology condition via the same receptors.…”

Section: The E Xpre Ss I On Of Lcn2 and Its Recep Tor S In The B R mentioning

confidence: 99%

Lipocalin‐2: Its perspectives in brain pathology and possible roles in cognition

Pinyopornpanish

Chattipakorn

2019

J Neuroendocrinology

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Lipocalin‐2 (LCN2) has been known to play an important role in pathological conditions, specifically in response to inflammation, infection and injury to cells. Recently, several research teams have been interested in investigating its association with cognition during the progression of pathology. Previous studies have demonstrated that LCN2 is not correlated with cognitive function under normal physiological conditions, although LCN2 has been negatively associated with cognition and some neuropathologies. Increasing LCN2 production is associated with reduced cognitive performance in a rodent model. However, further studies are needed to explore the potential underlying mechanisms of LCN2 on cognitive dysfunction, as well as its clinical relevance. This review aims to summarise the evidence available from in vitro, in vivo and clinical studies concerning the possible role of LCN2 on cognitive function following the onset of pathological conditions. Any contradictory evidence is also assessed and presented.

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Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer

Cited by 44 publications

References 81 publications

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age

Lipocalin‐2: Its perspectives in brain pathology and possible roles in cognition

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