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Amyloid-?1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic A? peptides. Amongst these, A?1-43 is more prone to aggregation and has higher toxic properties than the long-known A?1-42. However, a direct effect on A?1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. METHODS:N?=?1431?AD patients (n?=?280 early-onset (EO) and n?=?1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, A?1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with A?1-42 and A?1-40 CSF levels. The soluble sAPP? and sAPP? species were also measured for the first time in mutation carriers. RESULTS:A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF A?1-43 levels compared to controls (p?=?0.037;

SUBMITTER: Perrone F

PROVIDER: S-EPMC7488767 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Amyloid-β<sub>1-43</sub> cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

Perrone Federica F Bjerke Maria M Hens Elisabeth E Sieben Anne A Timmers Maarten M De Roeck Arne A Vandenberghe Rik R Sleegers Kristel K Martin Jean-Jacques JJ De Deyn Peter P PP Engelborghs Sebastiaan S van der Zee Julie J Van Broeckhoven Christine C Cacace Rita R

Alzheimer's research & therapy 20200911 1

<h4>Background</h4>Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ<sub>1-43</sub> is more prone to aggregation and has higher toxic properties than the long-known Aβ<sub>1-42</sub>. However, a direct effect on Aβ<sub>1-43</sub> in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.<h4>Methods</h4>N = 1431 A ...[more]

PMID: 32917274

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Project description:Introduction: Amyloid beta 1-43 (A?43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (A?42). Cerebrospinal fluid (CSF) A?43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF A?43 and established imaging biomarkers of Alzheimer's disease has never been assessed. Materials and Methods: In this observational study, CSF A?43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid A?43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF A?43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF A?43 and A?42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF A?43 average rho -0.73, A?42 -0.74. Both CSF A? peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF A?42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF A?43/42 and imaging biomarkers were significantly different for the two A? peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid A?43 appears to be strongly correlated with cerebral amyloid deposits in the same way as A?42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF A?43 performs better than the classical CSF biomarker A?42 for distinguishing SCD and MCI.

Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Dataset Information

Amyloid-?1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

Publications

Amyloid-β<sub>1-43</sub> cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

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