Cross-seeding between A?40 and A?42 in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Tran J
PROVIDER: S-EPMC5235972 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Cross-seeding between Aβ40 and Aβ42 in Alzheimer's disease.
Tran Joyce J Chang Dennis D Hsu Frederick F Wang Hongsu H Guo Zhefeng Z
FEBS letters 20161229 1
Aβ42 is the major component of parenchymal plaques in the brain of Alzheimer's patients, while Aβ40 is the major component of cerebrovascular plaques. Since Aβ40 and Aβ42 coexist in the brain, understanding the interaction between Aβ40 and Aβ42 during their aggregation is important to delineate the molecular mechanism underlying Alzheimer's disease. Here, we present a rigorous and systematic study of the cross-seeding effects between Aβ40 and Aβ42. We show that Aβ40 fibril seeds can promote Aβ42 ...[more]
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Project description:BackgroundDecreased concentrations of amyloid-? 1-42 (A?42) in cerebrospinal fluid (CSF) and increased retention of A? tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in A? metabolism. The CSF A?42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF A?42 alone.ObjectiveWe tested whether CSF A?42 alone or the A?42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results.MethodsCSF obtained from a mixed cohort (n?=?200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n?=?150 PET-negative, n?=?50 PET-positive according to a previously published cut-off) was assayed for A?42 and A?40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions.ResultsCSF A?42/40 corresponded better than A?42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p?<?0.0001) and a larger AUC (0.936 versus 0.814, respectively, p?<?0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases.ConclusionThe CSF A?42/40 ratio is superior to A?42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total A?.
| S-EPMC5147502 | biostudies-literature
Project description:BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAβ42 + /amyR - = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A - T - and in CSFAβ42 + /amyR - , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A - T - (β = 0.58; p < 0.001), CSFAβ42 + /amyR - (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.
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Project description:Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (A?) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or 'seed' promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding A?, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects A? aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates A? aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared with AD transgenic mice or AD transgenic animals with type 1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting that these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. These data provide a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.
| S-EPMC5495631 | biostudies-literature
Project description:Amyloid-beta (A?) is produced by the cleavage of amyloid precursor proteins in the cell membrane by ?-secretase and ?-secretase into a monomeric form with peptides of different lengths such as A?1-40 or A?1-42, which is then transformed into oligomeric and fibril forms and is considered to be one of the hallmarks of Alzheimer's disease (AD). The plasma concentrations of A?1-40 and A?1-42 are unstable after blood samples have been obtained. In order to examine the dynamic changes of plasma A?1-42 and A?1-40 in blood samples, we used fresh blood samples in ethylenediaminetetraacetic acid tubes from 32 clinically diagnosed AD patients. Each sample was subdivided into eight sub-samples, and levels of A?1-40 and A?1-42 were measured at 0 (baseline), 0.5, 1, 2, 3, 5, 8, and 24 h, respectively. All samples were incubated at 37°C before being measuring. The results showed that compared to baseline, 87.5 and 62.5% of the patients had higher plasma levels of A?1-42 and A?1-40 at 24 h, respectively. The patients with an increased amyloid level did not have a significantly different apo-lipoprotein E4 allele (APOE4) gene status for either A?1-40 (p = 0.422) or A?1-42 (p = 1.000). However, for plasma A?1-42, the APOE4 carriers had a significantly lower level than the non-carriers at baseline [31.2 ± 6.5 (mean ± SD) ng/ml vs. 50.4 ± 47.7 ng/ml, p = 0.031] and 0.5 h (37.5 ± 7.6 ng/ml vs. 51.9 ± 30.8 ng/ml, p = 0.043). There were no significant differences between the APOE4 carriers and non-carriers in plasma A?1-42 concentration at 1, 2, 3, 5, 8, and 24 h (p = 0.112, p = 0.086, p = 0.112, p = 0.263, p = 0.170 and p = 0.621, respectively). The A?1-40 level was related to disease severity as assessed using the clinical dementia rating (CDR) scale. Patients with advanced stages of dementia (CDR = 1 and CDR = 2) had a significantly higher A?1-40 level compared to those with very mild stage dementia (CDR = 0.5) at all time points (p < 0.05) except for 24 h (p = 0.059). Our findings illustrate the effects of APOE4 status on dynamic changes in plasma A?1-40 and A?1-42 levels, and significant associations between A?1-40 level and disease severity. Further studies are needed to investigate the exact mechanisms of how APOE4 affects the dynamic changes in plasma A?1-40 and A?1-42, and the association between A?1-40 and advanced dementia.
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Project description:The relationship between amyloid-? (A?) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A?42/40 ratio, not total A? level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ? precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A?42/40 ratio. Roles of A?42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A?42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high A?42/40) cells, not with I47F cells (low A?42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A?42/40 ratio in AD therapy.
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Project description:Amyloid ?-protein (A?) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid ?-protein (A?) variants were believed to begin at or after the canonical ?-secretase cleavage site within the amyloid ?-protein precursor. However, N-terminally extended forms of A? (NTE-A?) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of A?42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of similar morphology as A?42, but the half-time of aggregation (t1/2) increases exponentially with extension length. Monte Carlo simulations of model peptides suggest that the retardation is due to an underlying general physicochemical effect involving reduced frequency of productive molecular encounters. Indeed, global kinetic analyses reveal that NTE-A?42s form fibrils via the same mechanism as A?42, but all microscopic rate constants (primary and secondary nucleation, elongation) are reduced for the N-terminally extended variants. Still, A?42 and NTE-A?42 coaggregate to form mixed fibrils and fibrils of either A?42 or NTE-A?42 catalyze aggregation of all monomers. NTE-A?42 monomers display reduced aggregation rate with all kinds of seeds implying that extended termini interfere with the ability of monomers to nucleate or elongate. Cross-seeding or coaggregation may therefore represent an important contribution in the in vivo formation of assemblies believed to be important in disease.
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Project description:IntroductionHuntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40-42).MethodsA retrospective analysis of 66 HD patients with 40-41-42 CAG expansion was performed. Patients were investigated with the Unified Huntington's Disease Rating Scale (subitems I-II-III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher's test, t test and Pearson's correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression.ResultsThe age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups.ConclusionThere were no clinical differences between CO and LO subgroups with 40-42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.
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Project description:Evidence suggests that oligomers of the 42-residue form of the amyloid ?-protein (A?), A?42, play a critical role in the etiology of Alzheimer's disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of A?42 that occur at the earliest stages of aggregation. We observe features that can be attributed to a monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that A?42 hexamers and dodecamers quickly become the dominant oligomers after peptide solubilization, even at low (1 ?M) concentrations and short (5 min) incubation times. Soon after (?10 min), dodecamers are observed to seed the formation of extended, linear preprotofibrillar ?-sheet structures. The preprotofibrils are a single A?42 layer in height and can extend several hundred nanometers in length. To our knowledge this is the first report of structures of this type. In each instance the preprotofibril is associated off center with a single layer of a dodecamer. Protofibril formation continues at longer times, but is accompanied by the formation of large, globular aggregates. A?40, by contrast, does not significantly form the hexamer or dodecamer but instead produces a mixture of smaller oligomers. These species lead to the formation of a branched chain-like network rather than discrete structures.
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Project description:Mutations in the amyloid precursor protein (APP) gene and the aberrant cleavage of APP by ?-secretase are associated with Alzheimer's disease (AD). Here we have developed a simple and sensitive cell-based assay to detect APP cleavage by ?-secretase. Unexpectedly, most familial AD (FAD)-linked APP mutations make APP partially resistant to ?-secretase. Mutations that alter residues N terminal to the ?-secretase cleavage site A?42 have subtle effects on cleavage efficiency and cleavage-site selectivity. In contrast, mutations that alter residues C terminal to the A?42 site reduce cleavage efficiency and dramatically shift cleavage-site specificity toward the aggregation-prone A?42. Moreover, mutations that remove positive charge at residue 53 greatly reduce the APP cleavage by ?-secretase. These results suggest a model of ?-secretase substrate recognition, in which the APP region C terminal to the A?42 site and the positively charged residue at position 53 are the primary determinants for substrate binding and cleavage-site selectivity. We further demonstrate that this model can be extended to ?-secretase processing of notch receptors, a family of highly conserved cell-surface signaling proteins.
| S-EPMC4994064 | biostudies-literature